FOLFOX Chemotherapy Research Articles

Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.

Predictive value of ERCC1 and KRAS in colorectal cancer patients with FOLFOX chemotherapy.

588 Background: To determine the clinical significance of KRAS mutation and ERCC1 overexpression as a predictive factor of resistance in oxaliplatin based treatment. Methods: We retrospectively analyzed the clinicopathologic features, status of KRAS mutation and ERCC1 overexpression of 386 colorectal cancer patients who received curative intent surgery. Among them 84 patients were treated by FOLFOX regimen as the first line. Their disease-free survival and overall survival according to the KRAS and ERCC1 were analyzed. Results: About a quarter of patients (25.5%) were represented KRAS wild type with ERCC1 overexpression. Among the patients who treated by FOLFOX regimen, 73 patients were evaluated both of the KRAS and ERCC1. There were no significant differences of disease-free survival and overall survival according to KRAS status and ERCC1 expression each. Under the subgroup analysis, overall survival of ERCC1 overexpression group in wild type KRAS was poor than ERCC1 negative group (p=.029), but no significant difference was in mutant KRAS group (p=.671). Conclusions: Our results suggest that the KRAS wild type with ERCC1 overexpression would be associated with the resistance of oxaliplatin.If oxaliplatin based chemotherapy would beconsidered, status of KRAS mutation and ERCC1 overexpression should be evaluated.

SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC).

637 Background: SIRFLOX, an international multi-centre open-label RCT in first-line pts with non-resectable, liver-only or liver-dominant mCRC, showed that compared to FOLFOX (± bev) chemotherapy alone [arm A] FOLFOX (± bev) plus SIRT using Y-90 resin microspheres [arm B] did not improve overall PFS (median 10.2 v 10.7 months arm A v B, HR: 0.93; 95% CI 0.77–1.12; p = 0.429). However, liver PFS by competing risk analysis was improved with the addition of SIRT (median 12.6 v 20.5 months in arm A v B, HR: 0.69; 95% CI 0.55–0.90; p = 0.002). The current analysis examines patterns of disease progression and potential impact on the primary study endpoint. Methods: Site and pattern (intra/extra-hepatic) of first progression, and whether progression was due to growth of existing lesions or the appearance of new lesions, was judged by an independent reader blinded to study arm. Results: From Oct 2006 to Apr 2013, 530 pts were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases at study entry; 292 (55%) were stratified to receive bev. As of 31 Jan 2015, the total number of patients with disease progression in arm A v B were 178 and 166, respectively. The site of first progression was more frequently in the liver (± other sites) in arm A v B (92.1% v 72.3%; p < 0.001). Conversely, site of first progression was less frequent in the lung (± other sites) in arm A v B (19.1% v 42.8%; p < 0.001). A higher proportion of first progression occurred in the liver alone in arm A v B (77.0% v 52.4%; p < 0.001). Conversely, a lower proportion of first progression occurred only in non-liver sites, primarily lung, in arm A v B (7.9% v 47.7%; p < 0.001). Of patients with first progression in the liver, a higher proportion occurred in existing liver lesions (± extrahepatic sites) in arm A v B (72.5% v48.2%; p < 0.001). Conclusions: The addition of SIRT to FOLFOX chemotherapy alone (± bev) reduced the frequency at which first disease progression occurred in the liver. Where first progression did occur in the liver, the addition of SIRT led to this more frequently being due to the appearance of lesions not evident on baseline imaging. Clinical trial information: NCT00724503.

Synchronous rectal adenocarcinoma and splenic marginal zone lymphoma.

Synchronous cancers of different primary origin are rare. Here, we describe the case of a patient with concomitant diagnoses of rectal adenocarcinoma and splenic marginal zone lymphoma (smzl). A 57-year-old woman initially presented with abdominal pain. Physical examination and computed tomography demonstrated massive splenomegaly, and a complete blood count revealed microcytic anemia and lymphopenia. During the subsequent evaluation, she presented with hematochezia, melena, and constipation, which prompted gastroenterology referral. Subsequent endoscopic rectal ultrasonography revealed a T3N1 moderately differentiated rectal adenocarcinoma, with computed tomography imaging of chest, abdomen, and pelvis confirming no metastasis. Thus, the cancer was classified as clinical stage T3N1M0, stage iii. Bone marrow biopsy confirmed co-existing marginal zone lymphoma, and with the clinical presentation of massive splenomegaly, a diagnosis of smzl was made. The patient's management was individually tailored for simultaneous optimal treatment of both conditions. Concurrent treatment with neoadjuvant rituximab and 5-fluorouracil chemotherapy, with external-beam radiation therapy to the pelvis, was administered, followed by surgery consisting of en bloc splenectomy and distal pancreatectomy, and low anterior resection. The patient completed a standard course of adjuvant folfox (fluorouracil-leucovorin-oxaliplatin) chemotherapy and has remained disease-free for 7 years. To our knowledge, this report is the first to specifically describe simultaneous diagnoses of locally advanced rectal cancer and smzl. We also describe the successful combined neoadjuvant treatment combination of 5-fluorouracil, rituximab, and pelvic radiation.

FOLFOX chemotherapy as a cause of ventricular septal rupture after alcohol septal ablation for obstructive hypertrophic cardiomyopathy?

FOLFOX chemotherapy as a cause of ventricular septal rupture after alcohol septal ablation for obstructive hypertrophic cardiomyopathy?

Prognostic significance of the pre-chemotherapy lymphocyte-to-monocyte ratio in patients with previously untreated metastatic colorectal cancer receiving FOLFOX chemotherapy.

BackgroundAs a surrogate marker of systemic inflammation, the lymphocyte-to-monocyte ratio (LMR) is an independent prognostic factor for various malignancies. This study investigated the prognostic significance of the pre-chemotherapy LMR in patients with previously untreated metastatic colorectal cancer (mCRC) receiving chemotherapy.MethodsThe present study included newly diagnosed mCRC patients treated between January 2005 and December 2013 with FOLFOX chemotherapy, specifically oxaliplatin 180 mg/m2 on day 1, with leucovorin 400 mg/m2 administered as a 2-hour infusion before the administration of 5-fluorouracil 400 mg/m2 as an intravenous bolus injection, and 5-fluorouracil 2400 mg/m2 as a 46-h infusion immediately after 5-fluorouracil bolus injection. The LMR was calculated as the absolute count of lymphocytes divided by the absolute count of monocytes. COX proportional hazards analysis was performed to evaluate the association of LMR with survival outcomes.ResultsA total of 488 patients were included. Patients with high pre-chemotherapy LMR experienced significant improvements in progression-free survival (PFS, 9.2 vs. 7.6 months, P < 0.001) and overall survival (OS, 19.4 vs. 16.6 months, P < 0.001) compared with patients with low pre-chemotherapy LMR. Subsequent COX multivariate analysis showed that high pre-chemotherapy LMR (≥3.11) was an independent favorable prognostic factor for PFS and OS. Additionally, patients whose LMR remained high (high–high subgroup), increased (low–high subgroup), or decreased (high–low subgroup) following chemotherapy showed better results in terms of PFS and OS than patients whose LMR remained low (low–low subgroup) after chemotherapy.ConclusionsFor patients with previously untreated mCRC receiving FOLFOX chemotherapy, an elevated pre-chemotherapy LMR is an independent favorable prognostic factor for PFS and OS, and changes in the LMR before and after chemotherapy seem to predict the benefit of chemotherapy.

Hypertensive Profile of Metastatic Colorectal Carcinoma Patients Treated with Bevacizumab—A Prospective Study

Background: Bevacizumab is a recombinant humanized monoclonal antibody which targets Vasculoendothelial growth factor (VEGF)-A and prevents its binding to VEGF receptor 2 (VEGFR 2). It is approved in the first and second line treatment of metastatic colorectal cancer along with combination chemotherapy. Hypertension is an on-target and a common side effect of the treatment with bevacizumab. The true incidence of bevacizumab induced hypertension and its grading remains unclear due to paucity of prospective studies in this regard. In our institution, majority of metastatic colorectal cancer patients receive bevacizumab along with cytotoxic chemotherapy. In Indian, a context prospective study on this topic is negligible; so we find it to be of high importance. Objectives: We have conducted a prospective observational study of all metastatic colorectal patients receiving bevacizumab with chemotherapy and satisfying the eligibility criteria. The objective of the study was to assess the incidence and the pattern of hypertension. Materials & Methods: Patients receiving bevacizumab with FOLFOX (5 Fluorouracil, Calcium Leucovorin & Oxaliplatin) or CapeOX (Capecitabine & Oxaliplatin) chemotherapy for metastatic colorectal cancer were enrolled in the study; blood pressure was monitored before bevacizumab administration and also for the next seven days. This was done for all the chemotherapy cycles. Results: 100% of patients developed hypertension of any grade and 20% received treatment as a part of newly detected hypertension. Majority of the patients had grade 1 hypertension. Other grade of hypertension was grade 2. The blood pressure peaked on 6th day of bevacizumab administration. Conclusions: Hypertension of any grade may develop in bevacizumab treated patients. The incidence is very high and it may reach even up to 100% if prospectively and meticulously evaluated for longer period of time.

Oxaliplatin Pharmacokinetics and Pharmacodynamics in Three Metastatic Colorectal Cancer Patients with Hemodialysis

Aim: We investigated the safety and feasibility of L-OHP with chronic renal failure (CRF) on hemodialysis (HD) patients by examining the influence of pharmacokinetics and pharmacodynamics of oxaliplatin (L-OHP). Furthermore, we investigated. Methods: We present the results of three patients who were treated with modified FOLFOX6 (mFOLFOX6) chemotherapy for a mCRC with chronic renal failure on HD. We measured their plasma concentration of total platinum and free platinum. We evaluated whether L-OHP dose could be safely used for these patients. Different starting dose of L-OHP and 5-fluorouracil (50% and 75%) were used in these patients. Pharmacokinetics monitoring of platinum in plasma, plasma ultrafiltrates were measured these time schedule follow as: pre-chemotherapy infusion and 4 hours (pre-HD), 6 hours (half of HD), 8 hours (post HD), 48 hours after. Results: The 50% of peak concentrations (Cmax) was 0.27 μg・hr/mL ± 0.02 μg/mL and 75% Cmax was 0.41 μg・hr/mL ± 0.02 μg/mL. 50% of the area under the concentration versus time curve (AUC) was 14.8 μg・hr/mL ± 1.22 μg・hr/mL and 75% AUC was 22.43 μg・hr/mL ± 0.85 μg・hr/mL. Conclusion: We recognized these free plasma concentration which 50% dose of L-OHP was similar AUC between healthy and CRF patients. L-OHP pharmacokinetics and pharmacodynamics are altered in patients with CRF, but corresponding increase in L-OHP related hematological and non-hematological toxicities is not observed. It is important for cancer patients with CRF that the feasibility and efficacy of L-OHP combined chemotherapy should be determined.

FOLFOX chemotherapy can safely be given to neutropenic patients with early-stage colorectal cancer for higher dose intensity and fewer visits.

How does giving adjuvant FOLFOX chemotherapy to patients with early-stage colorectal cancer (ESCRC) regardless of the day-before absolute neutrophil counts (ANC) effect chemotherapy-induced febrile neutropenia (CIFN) rates, received dose intensity (RDI), and chemotherapy cycle delay? Does an ANC level predict future neutropenia? A retrospective chart review was conducted on all patients receiving adjuvant chemotherapy for ESCRC at a mid-sized community hospital in Toronto, Ontario, Canada between April 2005 and May 2014. All patients were under one medical oncologist. Day-before CBC data were collected along with other patient characteristics. CIFN was confirmed by hospital records. Inclusion criteria were met by 132 patients. Overall, 1074cycles of chemotherapy were analyzed. Six episodes of CIFN were observed. There was a significant difference in the average day-before ANC between patients who developed CIFN (1.4×10(9)/L, 95% CI 0.76-2.0×10(9)/L) and those who did not (2.9×10(9)/L, 95% CI 2.8-3.0×10(9)/L, p=0.03). The RDI for oxaliplatin was 0.95 and for 5-fluorouracil (5-FU) was 0.96. A total of 170cycles were given at day-before ANC <1.5×10(9)/L (range 0.1×10(9)/L-1.4×10(9)/L), and 24 were delayed for 1week for hematologic reasons. Cycles given with grade 2 neutropenia predicted higher grades of neutropenia with a sensitivity of 0.22 (95% CI 0.12-0.38). Adjuvant FOLFOX chemotherapy may be given in the setting of low day-before ANC to patients with ESCRC. The benefits include higher RDI and a reduced number of clinic visits for the patient.

Clinical value of gastric bare area for the prognosis of gastric fundus and cardia carcinoma

Objective To explore the clinical value of gastric bare area (GBA) for the prognosis of gastric fundus and cardia carcinoma. Methods The data of 82 patients with gastric fundus and cardia carcinoma from January 2010 to December 2011 were retrospectively analyzed. The patients were divided into group A (49 cases) with cancer cell invasion in GBA and group B (33 cases) without invasion in GBA. All the patients underwent D2 gastrectomy plus surgical resection of GBA and were treated by 6 cycles of postoperative FOLFOX-4 chemotherapy scheme. Postoperative follow-up and survival analysis were carried out for patients in both groups. Results According to survival analysis (Kaplan-Meier method), the postoperative 1-, 2- and 3-year cumulative survival rates of the patients in group A were 91.8 %, 57.3 % and 29.0 %, respectively, while those of the patients in group B were 93.9 %, 75.0 % and 48.2 %, respectively. The median survival times of the patients in group A and group B were 27.0 months and 36.0 months, respectively, which was demonstrated existing statistical significance(χ2 = 4.972, P= 0.026). Conclusions The prognosis of gastric fundus and cardia carcinoma patients with invasion in GBA by cancer cells is poor. Surgical resection of GBA may help to improve the prognosis of the patients with gastric fundus and cardia carcinoma. Key words: Stomach neoplasms; Gastric bare area; Survival analysis

Matched Pair Analysis of Sequential Short Course Radiation Therapy and FOLFOX Chemotherapy as Preoperative Therapy for Rectal Cancer: Improved DFS Compared to Institutional Controls Favors Near-Total Neoadjuvant Therapy

Matched Pair Analysis of Sequential Short Course Radiation Therapy and FOLFOX Chemotherapy as Preoperative Therapy for Rectal Cancer: Improved DFS Compared to Institutional Controls Favors Near-Total Neoadjuvant Therapy

Characterization of Rectal Cancer in Patients With Lynch Syndrome

Lynch syndrome (LS) resulting from a germline mutation in a DNA mismatch repair (MMR) gene is the most common form of hereditary colorectal cancer syndrome accounting for 3-5% of all colorectal cancer (CRC) cases. Mismatch repair deficient (dMMR) CRC is more commonly located in the proximal colon with decreasing incidence distally; thus, dMMR rectal cancer has not been well characterized. Our study aimed to describe the clinicopathologic features and outcomes of patients with LS-associated rectal cancer. Clinical genetics database review (1998–2014) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Clinical history and pedigree was extracted from medical records and Progeny. The Dworak classification was used for tumor regression grade (TRG) from grade 0 (no regression) to grade 4 (total regression). Of 192 LS patients with CRC, 27(14.1%) had RC. Mean age at RC diagnosis was 39.7 years (range, 22-59) with 18.5% having synchronous (n = 3) or metachronous (n = 2) colon cancer. In 85% of cases, the RC was the first LS-associated malignancy. While all RC patients met Revised Bethesda, only 48% met Amsterdam II criteria. Twenty-three rectal tumors were analyzed for MSI or defective MMR protein expression by immunohistochemistry; results were abnormal and concordant with germline test results in all cases. Nineteen (70%) patients harbored either an MSH2 or MSH6 gene mutation, with only 8 (30%) being MLH1 or PMS2 carriers. Of 25 RC patients with clinical data, 12 proceeded directly to surgery (7 stage 0/I; 5 stage II/III). Thirteen RC patients received preop neoadjuvant treatment for clinical stage II/III (n = 11) or IV (n = 2) disease, including 12 receiving chemoradiation and 6 also receiving FOLFOX chemotherapy. Downstaging of the primary tumor occurred in 69.2% (9/13) and of lymph nodes in 75% (9/12) of cases. All 13 RC patients underwent R0 resections and 10 patients had TRG available. Two (20%) patients had TRG 1, 7 (70%) had TRG 2 or 3 and 1 (10%) had TRG 4. One patient received preop FOLFOX for cT3N+ disease without chemoradiation with excellent clinical response initially; however, surgical pathology showed ypT4N2 disease with subsequent rapid development of metastatic disease. Another patient with cT4N2M1 (non-regional lymph node) progressed through induction FOLFOX, but after receiving chemoradiation was downstaged to ypT3N0M0. With a median follow-up of 4.6 years (range, 0.08-17.0), 2 had local and distant recurrences and 4 developed a subsequent LS-associated cancer. Although less common than colon cancer, rectal cancer may be the index cancer leading to a diagnosis of LS and appears to be overrepresented in MSH2/MSH6 gene mutation carriers. Further analysis to compare outcomes and prognosis with non-Lynch and sporadic dMMR rectal cancers is needed.

Prognostic influence of body mass index and body weight gain during adjuvant FOLFOX chemotherapy in Korean colorectal cancer patients.

BackgroundAsian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far.MethodsWe have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/ leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery.ResultsAmong a total of 522 patients, 35.7 % of patients were obese (BMI ≥ 25 kg/m2) and 29.1 % were overweight (BMI, 23–24.9 kg/m2) before surgery. 18.0 % of patients gained ≥ 5 kg and 26.1 % gained 2–4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (≥5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02–4.08, p = 0.043) in overweight and obese patients (BMI ≥ 23.0 kg/m2).ConclusionIn Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients.

Tumor regression after neoadjuvant chemotherapy in locally advanced colon cancer

Background. Our aim was to investigate efficacy of neoadjuvant chemotherapy in colon cancer based on tumor regression. Materials and methods . This retrospective study included colon cancer patients, who underwent treatment at the department of oncoproctology of Russian N. N. Blokhin Cancer Research Center during 2007–2014 and who received a minimum of 2 cycles of neoadjuvant chemotherapy. Primary endpoint was tumor regression. Tumor regression was analyzed separately considering treatment scheme, number of treatment cycles and presence of lymph node metastases. Results. 18 patients were included (9 male and 9 female). 9 patients had locally advanced T4N0–2M0 colon cancer and 9 patients had metastatic T3–4N0–2M1 colon cancer. 17 (94.4 %) patients had macroscopic signs of residual tumor. Grade 1 and 2 tumor regression (Dworak) was observed in 6 (33.3 %) and 10 (55.5 %) patients respectively. 2 (11.1 %) patients had no signs of tumor regression. Grade 2 tumor regression was most frequently (in 6/10 patients) observed after XELOX or FOLFOX chemotherapy. Conclusions. Neoadjuvant chemotherapy leads to tumor regression inn most colorectal cancer patients. In our group chemotherapy regimens including oxliplatin were more effective.

L08 - A Single Arm Clinical Trial to Assess the Efficacy and Safety of Panitumumab (Vectibix®) in combination with FOLFOX4 Chemotherapy as 1st line treatment in Subjects with Metastatic Gastric or Gastroesophageal Junction adenocarcinoma (VEGA trial). A multicenter Phase II SICOG trial 0802

L08 - A Single Arm Clinical Trial to Assess the Efficacy and Safety of Panitumumab (Vectibix®) in combination with FOLFOX4 Chemotherapy as 1st line treatment in Subjects with Metastatic Gastric or Gastroesophageal Junction adenocarcinoma (VEGA trial). A multicenter Phase II SICOG trial 0802

Appendiceal Goblet Cell Carcinoids: Management Considerations from a Reference Peritoneal Tumour Service Centre and ENETS Centre of Excellence

Background: Appendix goblet cell carcinoids are known to share histological features of adenocarcinoma and neuroendocrine tumours. Due to their low incidence, quality evidence is lacking for the management of these patients. Methods: We performed a single-centre retrospective study of patients with a confirmed diagnosis of appendiceal goblet cell carcinoid (GCC; 1996-2014). Patients were divided into curative intent (CI) and palliative intent (PI) cohorts. Our primary end point was overall survival (OS). Results: Seventy-four patients were eligible; 76% were treated with CI [surgery only (36%), cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC; 36%), adjuvant chemotherapy (20%) and a combination of CRS and HIPEC followed by adjuvant chemotherapy (9%)], and 23% had advanced-stage disease amenable to palliative treatment (chemotherapy or supportive care) only. Completion right hemicolectomy, performed in 64% of the CI cohort, did not impact on the relapse rate or disease-free survival. FOLFOX chemotherapy was used in both the adjuvant and palliative settings; safety was as expected, and we observed a high rate (60%) of disease control in the palliative cohort. The estimated median OS (all patients), disease-free survival (CI patients) and progression-free survival (PI patients) were 52.1 (95% CI 29.4-90.3), 75.9 (26.6-not reached) and 5.3 (0.6-5.7) months, respectively. Age and stage were independent factors associated with OS in the multivariable analysis. Tang classification showed a trend for impact on OS. No benefit from specific adjuvant approach was identified; however, selection bias for treatment approach was observed. Conclusion: Prospective trials are needed to define optimal approaches in GCC. All GCC patients should be managed by specialized centres due to their esoteric behaviour; we provide management considerations based on our experience and conclusions.

The clinical analysis of acute pancreatitis in colorectal cancer patients undergoing chemotherapy after operation.

Acute pancreatitis is a rare complication in postoperative colorectal cancer patients after FOLFOX6 (oxaliplatin + calcium folinate +5-FU [5-fluorouracil]) chemotherapy. In this paper, a total of 62 patients with gastrointestinal cancer were observed after the burst of acute pancreatitis. Surgery of the 62 cases of colorectal cancer patients was completed successfully. But when they underwent FOLFOX6 chemotherapy, five patients got acute pancreatitis (8.06%), four (6.45%) had mild acute pancreatitis, and one (1.61%) had severe acute pancreatitis, of which two were males (3.23%) and three females (4.84%). No patients (0.00%) had acute pancreatitis on the 1st day after chemotherapy; one patient (1.61%) got it in the first 2 and 3 days after chemotherapy; and three others (4.83%) got it in the first 4 days after chemotherapy. In the 62 patients with malignant tumors, the body mass index (BMI) was less than 18 (underweight) in six of them, with two cases of acute pancreatitis (33.33%); the BMI was 18–25 (normal weight) in 34 cases, with one case (2.94%) of acute pancreatitis; the BMI was 25–30 (overweight) in 13 cases, with 0 cases (0.00%) of acute pancreatitis; and the BMI was ≥30 (obese) in nine patients, with two cases of acute pancreatitis (22.22%). After symptomatic treatment, four patients were cured and one died; the mortality rate was 1.61%. Most of them appeared in the first 4 days after chemotherapy; the probability of this complication is significantly higher in slim and obese patients than in normal weight patients. Postoperative colorectal cancer patients after FOLFOX6 chemotherapy have a sudden onset of acute pancreatitis occult, especially in patients with severe acute pancreatitis; the symptoms are difficult to control, there is high mortality and it is worthy of clinician’s attention.

Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial – the PRODIGE 22 - ECKINOXE trial

BackgroundIn patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30 % of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.Methods/DesignPRODIGE 22 - ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50 % prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.Trial RegistrationNCT01675999 (ClinicalTrials.gov)

Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

A glucose-conjugate of (trans-R,R-cyclohexane-1,2-diamine)-2-fluoromalonato-platinum(II) complex (Glu-Pt) is designed to target tumor-specific active glucose transporters (GLUTs). Despite of very high water solubility, Glu-Pt exhibits improved cytotoxicity as compared to oxaliplatin. In this study, we investigated the in vivo toxicity profiles with the maximum tolerated dose (MTD) evaluation followed by antitumor efficacy study in leukemia-bearing DBA/2 mice. Glu-Pt showed 6-fold increase in the MTD and was more efficacious against mouse L1210 ascetic leukemia than oxaliplatin at equitoxic doses. To explore the combination effect of Glu-Pt and compare with oxaliplatin-based FOLFOX chemotherapy, we investigated the two-component synergistic antitumor activity of Glu-Pt with folinic acid (FA) and 5-fluorouracil (5-FU) respectively in five human cancer cell lines followed by a comparison study with oxaliplatin in a fixed three-component in vitro FOFLOX combination. As the result, Glu-Pt exhibited superior synergistic cytotoxicity compared to oxaliplatin. Flow cytometry-based cell cycle and apoptosis study demonstrated that Glu-Pt follows the same mechanistic principles as of oxaliplatin. Glu-Pt monotherapy and its combination with FA and 5-FU may result in improved efficacy over oxaliplatin and FOLFOX regimen. The study provides fundamental data supporting the potential of Glu-Pt as a drug candidate for further (pre)clinical development.

P0031 Use of FOLFOX4 regimen in stage IV cervical cancer: A pilot study

Background We performed a phase 2, single arm, open-label study of FOLFOX4 (oxaliplatin/fluorouracil/leucovorin) chemotherapy as palliative treatment in patients with metastatic cervical cancer to assess its efficacy and safety. Methods The patients recruited for this study were 18–65 years old had metastatic cervical cancer, prior radiotherapy treatment, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, life expectancy more than 6 months, adequate haematological, renal, and hepatic functions, and were able to comply with scheduled follow-up and with management of toxicity. Thirty patients were enrolled from December 2011, to January 2012. All patients received FOLFOX4 (oxaiplatin 85 mg/m2 on day 1, fluorouracil 400 mg/m2 intravenous push on day 1–2, fluorouracil 600 mg/m2 intravenous drip in 22 h on day 1–2, and folinic acid 200 mg/m2 intravenous push on day 1–2). Outcomes were treatment response after six and 12 cycles of FOLFOX4, and every 3 months thereafter, according to World Health Organisation (WHO) criteria and Response Evaluation Criteria in Solid Tumours (RECIST) guidelines, and toxicity. Findings The mean age was 51 years (range 24–64), and 80% of patients had squamous cell metastasis from cervical cancer. 70% had metastasis at a distant lymph node. 59% of patients received at least six cycles of FOLFOX4. Nine patients (31%) achieved an objective response. At the mean follow-up time of 12.8 months, 1-year progression-free and overall survival was 20.7% and 65.5%, respectively. The most common grade ⩾ 2 toxicities during chemotherapy were fatigue (48.3%) and anaemia (37.9%). One patient died during the first cycle of FOLFOX4 due to a non-cancer cause. Interpretation FOLFOX4 regimen in metastatic cervical cancer is feasible and of reasonable toxicity.