Christine Cripps

Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144

PURPOSE Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens. PATIENTS AND METHODS After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery. RESULTS Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3. CONCLUSION All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.

Combination Chemotherapy and ALVAC-CEA/B7.1 Vaccine in Patients with Metastatic Colorectal Cancer

Purpose: The combination of vaccines and chemotherapy holds promise for cancer therapy, but the effect of cytotoxic chemotherapy on vaccine-induced antitumor immunity is unknown. This study was conducted to assess the effects of systemic chemotherapy on ALVAC-CEA/B7.1–induced T-cell immunity in patients with metastatic colorectal cancer. Experimental Design: Patients with metastatic colorectal cancer were treated with fluorouracil, leucovorin, and irinotecan and were also given ALVAC-CEA/B7.1 vaccine with or without tetanus toxoid adjuvant. Eligible patients were randomized to ALVAC followed by chemotherapy and booster vaccination (group 1), ALVAC and tetanus toxoid followed by chemotherapy (group 2), or chemotherapy alone followed by ALVAC in patients without disease progression (group 3). Humoral immune responses were measured by standard ELISA assay, and carcinoembryonic antigen (CEA)-specific T-cell responses were measured by IFN-γ enzyme-linked immunospot assay. Results: One hundred eighteen patients were randomized to receive either ALVAC before and concomitantly with chemotherapy (n = 39), ALVAC with tetanus adjuvant before and concomitantly with chemotherapy (n = 40), or chemotherapy followed by ALVAC (n = 39). Serious adverse events were largely gastrointestinal (n = 30) and hematologic (n = 24). Overall, 42 patients (40.4%) showed objective clinical responses. All patients developed antibody responses against ALVAC, but increased anti-CEA antibody titers were detected in only three patients. Increases in CEA-specific T cells were detected in 50%, 37%, and 30% of patients in groups 1, 2, and 3, respectively. There were no differences in clinical or immune responses between the treatment groups. Conclusion: The combination of ALVAC-CEA/B7.1 vaccine and systemic chemotherapy has an acceptable safety profile in patients with metastatic colorectal cancer. Systemic chemotherapy did not affect the generation of CEA-specific T-cell responses following vaccination.

PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy.

Purpose The standard of care for second-line therapy in patients with advanced pancreatic cancer after gemcitabine-based therapy is not clearly defined. The CONKO-003 phase III study reported a survival benefit with second-line fluorouracil (FU) and oxaliplatin using the oxaliplatin, folinic acid, and FU (OFF) regimen. 1 PANCREOX was a phase III multicenter trial to evaluate the benefit of FU and oxaliplatin administered as modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) versus infusional FU/leucovorin (LV) in this setting. Patients and Methods Patients with confirmed advanced pancreatic cancer who were previously treated with gemcitabine therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. A total of 108 patients were randomly assigned to receive biweekly mFOLFOX6 or infusional FU/LV until progression. Progression-free survival (PFS) was the primary end point. Results Baseline patient characteristics were similar in both arms. No difference was observed in PFS (median, 3.1 months v 2.9 months; P = .99). Overall survival (OS) was inferior in patients assigned to mFOLFOX6 (median, 6.1 months v 9.9 months; P = .02). Increased toxicity was observed with the addition of oxaliplatin, with grade 3/4 adverse events occurring in 63% of patients who received mFOLFOX6 and 11% of those who received FU/LV. More patients in the mFOLFOX6 arm withdrew from study due to adverse events than in the FU/LV arm (20% v 2%), whereas the use of postprogression therapy was significantly higher in the FU/LV arm (25% v 7%; P = .015). No significant differences were observed in time to deterioration on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health scale. Conclusion No benefit was observed with the addition of oxaliplatin, administered as mFOLFOX6, versus infusional FU/LV in patients with advanced pancreatic cancer previously treated with first-line gemcitabine.

A cost comparison of oral tegafur plus uracil/folinic acid and parenteral fluorouracil for colorectal cancer in Canada

AbstractBackground: Two randomised, controlled trials (n = 1396) comparing (i) intravenous fluorouracil (FU) plus oral folinic acid (leucovorin) and (ii) oral tegafur plus uracil (UFT) plus folinic acid for the treatment of metastatic colorectal carcinoma found both regimens to have equivalent efficacy in terms of survival, tumour response and time to disease progression. The UFT/folinic acid regimen was associated with a better toxicity profile than FU/folinic acid. Objective: To determine the comparative frequencies and costs of healthcare resources utilised in the treatment of patients with these two regimens from a hospital and government perspective. Design: A cost-minimisation analysis of a subgroup of patients from the trials (n = 154) was conducted. Costs considered included those for hospital admissions, outpatient clinics, laboratories, imaging modalities, other diagnostic procedures, physician resources, other health professionals, other procedures such as surgery and transfusion, and concomitant medications. The cost of study medications was not included in the analysis. The endpoint was a total average cost per patient per treatment and per cycle. Results: Patients on the oral UFT regimen had fewer outpatient clinic visits and used fewer laboratory resources than patients treated with FU. However, those on the oral regimen had more days of hospitalisation than the patients treated with the intravenous regimen. Patients treated with UFT used 21% less concomitant medication; however, in both groups these medications accounted for a similar percentage compared with the total costs of the treatment. Physicians’ fees were similar for both groups but patients treated with UFT were seen more often by an attending physician. Patients on the UFT regimen visited outpatient oncology clinics less often and this was reflected by a maximum 826 Canadian dollars (

Outpatient 5-Fluorouracil, Folinic Acid and Cisplatin in Patients with Advanced Esophageal Carcinoma

Can; 1996 values) total cost savings per patient per cycle and

Mitoxantrone, prednimustine, and vincristine for elderly patients with aggressive non‐Hodgkin's lymphoma

Can3221 per patient per treatment. An efficiency analysis showed that the use of the UFT/folinic acid regimen saved 4.5 hours per patient per month in the chemotherapy treatment unit compared with the FU regimen. Conclusions: In regard to the two therapeutic approaches, the cost of treatment per patient and per cycle using oral UFT/folinic acid was less than that using intravenous FU/folinic acid.

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck.

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation

Elderly patients with intermediate‐ or high‐grade non‐Hodgkins lymphoma have a worse outcome than those who are younger than 60 years. It has been shown that aggressive combination chemotherapy is poorly tolerated in older patients resulting in a subsequent decrease in dose intensity. A phase II trial was conducted with mitoxantrone, prednimustine, and vincristine (NSO) in this group of patients. NSO consists of mitoxantrone 12 mg/M2 intravenously on day one, vincristine 1.4 mg/M2 intravenously on day 1 (maximum dose of two mg), and prednimustine 100 mg/M2 orally once a day for four days. NSO was repeated every 21 days. Thirty‐six patients were able to be evaluated. There were 18 males and 18 females with the median age of 71 (range 60–85). NSO was well tolerated and nonhematological toxicities were uncommon. More than 80% of the patients received 90% or greater of the intended dose. The complete response rate was 60.6% and partial response was 21.8%. At 60 months the Kaplan‐Meier estimate of progression‐free survival was 47.9% (standard error 8.6%) and actual survival was 40.6% (standard error 8.8%). There were no differences in outcome between those with performance status (PS) of zero or one and those with PS > 1. NSO is well tolerated by elderly patients including those with PS > 1. These results compare favorably with other combinations in elderly patients with aggressive non‐Hodgkins lymphoma. Am. J. Hematol. 59:156–160, 1998.

Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer

A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.

Retrospective comparative analysis of 5FU + low-dose folinic acid vs. 5FU + high-dose folinic acid in the treatment of metastatic colorectal cancer the Ottawa experience

Purpose: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)–based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. Experimental Design: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3–5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). Conclusion: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule. Clin Cancer Res; 21(7); 1583–90. ©2015 AACR.