Modified De Gramont Research Articles

A phase I dose-escalation study of an all-in-one 5-fluorouracil and leucovorin co-formulation administered after failure of standard treatment.

140 Background: 5-fluorouracil (5-FU) and its biomodulator leucovorin (LV) are an efficacious treatment option for various solid tumours, and are considered the backbone of therapy for colorectal cancer. Standard administration schedules require sequential administration of the two agents due to their chemical incompatibility; given the importance of LV in modulating 5-FU activity, their simultaneous administration is expected to enhance anti-tumour efficacy. Deflexifol is an all-in-one injectable reformulation of 5-FU and LV at physiological pH. An initial phase I trial demonstrated the safety and efficacy of Deflexifol when administered as a bolus or infusion, with a maximum tolerated dose (MTD) of ≥25% more 5-FU than established for standard regimens. This subsequent phase I study sought to investigate Deflexifol administered as a combined bolus and infusion schedule. Methods: Patients with advanced malignancy who had failed standard treatment were administered Deflexifol as a bolus followed by a continuous 46-hr infusion. The infusional dose was escalated across four levels (2400 mg/m2 to 3800 mg/m2) in the absence of Dose Limiting Toxicity using a traditional 3+3 design; the bolus dose was fixed at the previously declared MTD of 525 mg/m2. The stated Deflexifol dose represents the dose of standard 5-FU delivered. Primary trial objectives were to determine the safety and tolerability of a bolus plus infusion regimen of Deflexifol, with a secondary objective to determine the pharmacokinetics and MTD. Efficacy was an exploratory objective. Results: Nineteen patients with mainly colorectal (n=13) and breast (n=4) cancers were enrolled and treated with Deflexifol. Approximately two-thirds of patients had previously received fluoropyrimidine treatment. Deflexifol was generally well tolerated, with the MTD declared as a 525 mg/m2 bolus plus 3400 mg/m2 infusion. Treatment-related toxicities were consistent with standard 5-FU/LV therapy; the most frequent Grade 1/2 adverse events were fatigue, mucositis, and diarrhea. Grade ≥3 adverse events were reported in 6/19 patients, including mucositis (2/19) and haematological toxicity (5/19). One treatment-related death occurred at the highest infusion dose level of 3800 mg/m2 due to haematological toxicity. Quantifiable 5-FU and LV concentrations were exhibited at all time-points. Disease control, including one partial response, was achieved in 9/13 evaluable patients. Conclusions: Deflexifol is safe and well tolerated at doses of 5-FU up to 40% higher than typically administered by the standard modified de Gramont regimen. 5-FU and LV co-exposure extended throughout the entire dosing period, substantially longer than reported for standard treatment. Disease control was achieved in 69% of patients. Clinical trial information: ACTRN12619001533189 .

Should we still be using bolus 5-FU prior to infusional regimens in gastrointestinal cancers? A practical review.

5-fluorouracil (5-FU), a pyrimidine analogue with antimetabolite activity, is one of the most widely used drugs in Oncology and many different regimens have been described regarding its use. Nowadays, the modified de Gramont is the most popular schedule of 5-FU to treat gastrointestinal cancers and may be given either alone or combined with irinotecan, oxaliplatin and monoclonal antibodies. The true clinical value of bolus 5-FU right before infusional regimens remains to be determined since no randomized trials have addressed this issue. This manuscript aims to review the history of 5-FU, its mechanism of action and the data exploring the role of bolus 5-FU.

Cisplatin-Modified De Gramont in Second-Line Therapy for Pancreatic Adenocarcinoma

In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil + leucovorin (CFL) according to the modified de Gramont schedule is the treatment of choice in second line for metastatic pancreatic cancer. We retrospectively analyzed survival data in 2 Belgian centers in a nonselected population. Between January 2004 and October 2011, 48 patients with histologically proven recurrent or unresectable pancreatic adenocarcinoma who had received CFL as second-line treatment were identified. We retrospectively analyzed the following parameters: progression-free survival (PFS1 and PFS2) for each line (after the start of first and second line), overall survival (OS), and growth modulation index. The median PFS1 was 5.4 months (95% confidence interval [CI], 4.1-6.6). The median PFS2 was 3.6 months (95% CI, 2-5.2). The median OS was 12 months (95% CI, 9.3-14.7). Twenty-three percent of patients had a growth modulation index >1.33. We show an OS of 12 months with gemcitabine in first-line and CFL in second-line therapy for pancreatic cancer. Sequential therapy with good OS and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer.

Adjuvant chemoradiation (CRT) for high-risk gastric cancer (GC): Single-center experience using infusional 5-fluorouracil (5FU) and radiotherapy (RT).

e14571 Background: Postoperative CRT is a standard treatment option for fully resected high risk GC. Adjuvant CRT using bolus 5FU significantly improved overall (OS) and disease free survival (DFS) versus surgery alone. However, this regimen is associated with significant toxicity and poor tolerability. Methods: Sixty eight patients (pts) with high risk GC were referred following surgery for adjuvant CRT. The treatment comprised six cycles of the “modified de Gramont”regimen [leucovorin: 350 mg iv (d1) and 5-FU: 400 mg/m2 iv-bolus (d1), 2,800mg/m2 over 46 hours]; the third and fourth cycle of chemotherapy given concurrently with RT as follows: total dose of RT 4,500 cGy in 25 fractions of 180 cGy. Pts were evaluated retrospectively for toxicity, DFS and OS. Results: With a median follow-up period of 32 months (mo; range: 5–90), 68 patients (36 men, 32 women), median age 59 years (range: 30-76) were treated; stage IB: 4,4% (3/68 pts), IIA:7,35% (5/68 pts), IIB:13% (9/68 pts), IIIA: 11,7% (8/68 pts), IIIB: 30,8% (21/68 pts), IIIC: 32,3% (22/68 pts). The median DFS and OS were 25,2 and 32 mo, respectively. Three year DFS and OS were 24% and 29%. Grade III or higher myelotoxicity was: neutropenia 16% (11 pts); two pts grade IV neutropenia, thrombocytopenia 3% (2 pts). Grade III or higher non hematologic toxicity were: diarrhea 19% (13pts), vomiting 3% (2 pts), stomatitis/esophagitis 8% (6 pts) and constipation 3% (2 pts). There was no grade IV non hematologic toxicity. Fifty-three pts (78%) completed the treatment. Discontinuation was necessary in 5 pts due to diarrheas, 3 due to neutropenia, 3 due to performance status deterioration, 1 patient due to infection, 1 due to arythmia and 2 pts after informed consent withdrawal. Two pts died during treatment: one from possible/unconfirmed cardiovascular event and the other one due to sepsis. Conclusions: Despite a relatively short median follow-up and small sample size, our findings suggest that this regimen could be an alternative option, with favorable toxicity and tolerability in patients with fully resected high risk GC.

Cytotoxic chemotherapy for incurable colorectal cancer: living with a PICC‐line

(i) To determine which aspects of living with a peripherally inserted central catheter (PICC) line cause Modified de Gramont (MdG) patients most difficulty. (ii) To explore MdG patients' views of the PICC-line experience. (iii) To determine if patients view PICC-lines as a benefit or a burden when receiving ambulatory MdG chemotherapy. A two-stage, descriptive study. Phase 1 comprised semi-structured interviews. Phase 2 surveyed the MdG population. Phase 1 interview data informed the Phase 2 questionnaire. The setting was a West of Scotland Cancer Care Centre and the sample was: Phase 1, a convenience sample of 10 MdG patients; Phase 2, 62 consecutive patients. A response rate of 93.9% for Phase 2. The majority of PICC-line patients held favourable views towards having a PICC-line and adapted well with minimal disruption to daily life. Concerns were evident regarding coping at home with a PICC-line, chemotherapy spillage, dealing with complex information and the responsibility of patients/carers regarding PICC-line management. Patients preferred ambulatory chemotherapy to in-patient treatment. PICC-lines should be considered for more chemotherapy patients but service development is necessary to ensure individual needs are addressed. Contributes to the PICC-line literature by providing a national patient perspective on a range of daily living activities (DLAs). PICC-line patients prefer out-patient ambulatory chemotherapy rather than in-patient treatment. The longer a patient has a PICC-line, the more able they are to manage activities such as dressing. Concerns remain over chemotherapy spillage, partner/carer responsibility for PICC-line maintenance and the proper balance between required information and what the patient wants to know.

Sinusoidal obstruction syndrome (veno-occlusive disease) in a patient receiving bevacizumab for metastatic colorectal cancer: a case report

IntroductionWe present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease) (SOSVOD). Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD.Case presentationA 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg) was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised.ConclusionWe need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease) and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.

A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers

The prognosis of advanced biliary tract carcinoma is poor with chemotherapy limited to a palliative role. This randomised study was designed to evaluate the effectiveness of a new liposomal thymidylate synthase inhibitor (TSI), OSI-7904L, in parallel with a modified de Gramont regimen of 5-FU/LV in patients with advanced biliary cancer. Patients with previously untreated advanced or metastatic carcinoma of the biliary tract were randomised to receive either OSI-7904L 12 mg/m2 intravenously every 21 days or a modified de Gramont schedule of 5-FU/LV (intravenous l-LV 200 mg/m2, bolus 5-FU 400 mg/m2 and a 46-h infusion of 5-FU 2,400 mg/m2) every 14 days. Twenty-two patients were randomised, 11 to each group. No patients responded in the OSI-7904L arm, while one patient achieved a partial response in the 5-FU/LV arm. The rates of disease stabilisation were 4/11 (OSI-7904L) and 10/11 (5-FU/LV). Both treatment arms were generally well tolerated. These results show that the activity of OSI-7904L is below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilisation. A simplified de Gramont schedule appears to have marginally more activity. Both treatments were well tolerated.

Fluorouracil, oxaliplatin and CPT-11 (irinotecan), use and sequencing (MRC FOCUS): A 2135-patient randomized trial in advanced colorectal cancer (ACRC)

3518 Background: This multicenter, open randomized trial assesses the effect on overall survival (OS) and quality of life of the planned sequencing of the first two cytotoxic drugs (fluorouracil (FU) plus one other) received by patients (pts) with inoperable ACRC. It compares three approaches: sequential single agents (FU first then change to second drug); sequential single/combination (FU then add a second drug); or 1st-line combination. It also compares irinotecan (Ir) and oxaliplatin (Ox) combinations. Methods: Pts had PS 0–2; GFR >50; ALP <5 x ULN; bili <1.25 x ULN. Randomization was 2:1:1:1:1 to: Plan A (reference): MdG (Modified de Gramont: leucovorin; FU bolus + 48 hr infusion; q2w) until treatment failure, then 2nd-line Ir; Plans Bir and Box: MdG until treatment failure, then 2nd-line IrMdG or OxMdG respectively; Plans Cir and Cox: 1st-line IrMdG or OxMdG. Primary endpoint was OS, 2100 pts giving 80% power (α = 0.01) to detect a difference of 22.5% vs 15% in 2 yr OS of each plan against Plan A. Results: 2135 pts entered, May’00 - Dec’03, at 61 centres, median age 64 yrs; 92% PS 0–1. With 1435 deaths to date, the primary comparisons, of OS for each plan (Bir, Box, Cir, Cox) versus Plan A, show trends to improvement (HR 0.92, 0.91, 0.86, 0.96 respectively) but all are non-significant (all p > 0.05). Grouped comparison of OS in Plans B (712 pts) with Plan A (710 pts) has a HR of 0.91, 95% CI (0.81, 1.04) p=0.157 in favour of B. The comparison of OS in grouped Plans C (713 pts) with Plan A has a HR of 0.91 (0.80, 1.03) p=0.134 favouring C. Comparison of Plans B with Plans C has a HR of 1.00 (0.88, 1.14) p=0.993. OS does not differ significantly between Ox and Ir in plans B and C. Compared with Plan B, Plan C gave a higher 1st-line RR (54% vs 29%) and PFS (median 8.7 vs 6.6 months) but shorter time to failure of the Plan (median 9.1 vs 11.6 months) (all p<0.001). Conclusions: Slightly increased survival was seen with combination chemotherapy, whether given 1st line or 2nd line, but this does not reach conventional levels of statistical significance. However, 1st-line combination chemotherapy did not improve OS compared with the same combinations deferred until 2nd line. Mature data will be presented at the meeting. No significant financial relationships to disclose.

Colorectal cancer in 2003: state of the art and new developments

Colorectal cancer (CRC) accounts for 10–12% of all cancers and is second in the league of cancer deaths for men and women in western countries. In Western Europe there were more than 200,000 new cases of CRC and over a 100,000 deaths in the year 2000. Despite increased knowledge about the etiology of the disease and improved treatment strategies nearly 50% of patients still die of their disease. Furthermore, the main cause of death is not recurrence at the primary site, but disease spread, predominantly to the liver. The 5-year survival for patients with metastatic CRC is less than 5%, and while patients with resectable metastases have a 5-year survival of 30%, resectable patients currently represent only 15–20% of patients with liver metastases. The standard therapy for patients with advanced CRC remains palliative 5-fluorouracil (5-FU)-based systemic chemotherapy, which is administered with the aim of improving survival and quality of life (QoL). New combination regimens such as irinotecan/5-FU/folinic acid (FA) and oxaliplatin/5-FU/FA have improved survival [1–5] (Table 1). The recently reported EORTC trial of K€ ohne et al. [5] using irinotecan in combination with the German AIO 5-FU/FA regimen, has produced one of the highest median survival times for first-line chemotherapy in this setting with a median survival time of 20.1 months. The recently published study of the sequential administration of two combination regimens showed that the two regimens FOLFIRI (irinotecan/ 5-FU/FA [modified de Gramont]) and FOLFOX (oxaliplatin/5-FU/FA [modified de Gramont]) were essentially similar with both achieving high response rates (RRs) and impressive survival when either regimen was administered first-line followed by the other second-line [6]. Patients receiving FOLFIRI followed by FOLFOX achieved a RR of 56% first-line with a median overall survival (OS) of 21.5 months whilst patients receiving FOLFOX followed by FOLFIRI achieved a RR of 54% and a median OS of 20.6 months Table 2 [6]. These

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

To evaluate the clinical and cost-effectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5-fluorouracil/folinic acid (5-FU/FA) regimens. Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5-FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand-foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve health-related quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at 2111 pounds and 3375 pounds, respectively, compared with the total treatment cost for the Mayo regimen of 3579 pounds. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were 3684 pounds and 6155 pounds, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be 1461 pounds and 209 pounds, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be 1353 pounds and 101 pounds, respectively, and over the inpatient de Gramont regimen were estimated to be 4123 pounds and 2870 pounds, respectively. The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data.

A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified ‘Modified de Gramont’ (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m−2), then ambulatory 46-h fluorouracil infusion (2000–3600 mg m−2, cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m−2. Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m−2 bolus + 2800 mg m−2 46-h infusion. A lower dose of 400 mg m−2 bolus + 2400 mg m−2 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC0–48 h) at this lower dose is equivalent to dG. With OxMdG, grade 3–4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial.British Journal of Cancer (2002) 87, 393–399. doi:10.1038/sj.bjc.6600467 www.bjcancer.com© 2002 Cancer Research UK