Mayo Regimen Research Articles

Chemotherapy Compliance and Tolerance in Elderly and Non-Elderly Patients with Colorectal Cancer: A Single Institution Study

The objectives of this retrospective, observational study are to compare the compliance and tolerance rate between elderly and non-elderly patients with colorectal cancer, and to ascertain the stage at presentation. All adult patients with diagnosis colorectal cancer who received first line chemotherapy (adjuvant or palliative) between January 2017-January 2019 were included. Data on demographic, clinic-pathological, treatment and patient outcome were collected. Toxicity data was collected as they appear. These data were then analyzed using IBM®SPSS® Statistics Version 24. Sixty-four patients were included. There were almost equal numbers of elderly and non-elderly patients. Thirty-five patients were Malay (54.7%), Chinese 26 (40.6%) and Indian 3 (4.7%). Their age ranges from 38-82 years old. Most patients received FOLFOX regimen (73.4%), followed by Mayo regimen and capecitabine (10.9% each). There was no significance difference in the type of chemotherapy and number of cycles given. The majority received combination therapy rather than single therapy. There was no difference in the terms of toxicity between the study populations. Thirty-three percent of elderly and thirty-five percent of non-elderly patients had no documented chemo-toxicity. The most common toxicity is neutropenia, followed by thrombocytopenia and anaemia. In total, 25% (16 patients) did not complete their chemotherapy for various reasons. Nine were elderly patients (56.3%). Presentation at Stage 3 and 4 accounted for 70.3% (45 patients) of the study population. Elderly colorectal cancer patients’ should be treated with equal therapeutic opportunities as their younger counterparts. Biological age should be considered when deciding treatment regime rather than chronological age.

Cost-effectiveness of adjuvant chemotherapy for stage III colon cancer in the South African public healthcare setting.

e18849 Background: Colon cancer incidence and mortality rates are increasing in low- and middle-income countries, such as South Africa (SA). Adjuvant chemotherapy after curative resection for stage III colon cancer prolongs overall survival, but it is unclear which regimen is most cost-effective in resource-constrained settings, such as the SA public healthcare system. Methods: A decision-analytic Markov model was developed to compare lifetime costs and health outcomes for 60-year-old stage III colon cancer patients treated with six adjuvant chemotherapy regimens in a public hospital in SA: fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for 3 and 6 months, capecitabine and oxaliplatin (CAPOX) for 3 and 6 months, capecitabine for 6 months, and fluorouracil/leucovorin (5-FU/LV; Mayo regimen) for 6 months. Transition probabilities were derived from clinical trials to estimate risks of toxicity, disease recurrence, and survival. Costs from a SA societal perspective and utility estimates were obtained from literature and local expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) in international dollars (I$) per disability-adjusted life year (DALY) averted, with a willingness-to-pay (WTP) threshold of one times the 2020 GDP per capita of SA (I$13,006.57; ZAR89,225). Results: Our model found CAPOX for 3 months to be the most cost-effective strategy, at a lifetime cost below the local WTP threshold (I$5,380.82; ZAR36,912.44) and 5.74 DALYs averted, compared to no chemotherapy. FOLFOX for 6 months was also on the efficiency frontier, with a higher total cost (I$22,747.47; ZAR156,047.64) and 0.18 additional DALYs averted (ICER = I$99,021.35/DALY averted). All other strategies were absolutely dominated. One-way sensitivity analyses found that FOLFOX for 6 months is optimal when the administration cost (i.e.: port and pump) falls to 20% of the base case price. Conclusions: In the SA public healthcare system, CAPOX for 3 months is the most cost-effective adjuvant treatment for stage III colon cancer. FOLFOX for 6 months, with a greater effectiveness, may be cost-effective if the administration cost decreases significantly. The optimal strategy in other settings may vary according to the local WTP threshold.[Table: see text]

CHEMOTHERAPY IN RECTAL CANCER

The aim: To evaluate and analyze early and late results of treatment of patients with rectal cancer after chemotherapy. Materials and methods: The study is based on the results of observation of 779 patients with stage II, III and IV rectal cancer (RC) who were divided into groups according to the chemotherapy treatment. Results: In the course of chemotherapy treatment of RC patients, most of them received the FOLFOX regimen treatment – 87 patients (43.5%). 40 people (20%) received Mayo regimen. 36 patients (18%) underwent FOLFIRI regimen. Another 33 patients received the XELOX regimen chemotherapy (16.5%). In four cases, patients underwent Tegafur monotherapy (2%). Conclusions: The obtained data for patients with stage III RC showed that at all studied time intervals, the highest percentage of surviving patients was recorded in those who received chemotherapeutic treatment according to the FOLFOX regimen. In patients with stage II RC, the most effective was Mejo regimen – 30.7% (survived patients for the 5 year observation).

Toxicity and survival outcomes of adjuvant chemoradiation for gastric and gastroesophageal junction cancer patients treated in period 2006-2009: an institutional experience.

Surgical resection is the mainstay of gastric or gastroesophageal junction cancer treatment and has curative potential for patients with early-stage disease. In order to improve the poor survival rates, there are two complementary treatment strategies used at most - perioperative chemotherapy based on UK Magic trial or adjuvant chemoradiation based on INT-0116 trial. Daily treatment decision making should be led also by institutional experiences with toxicity evaluation. We evaluated survival and toxicity outcomes of 47 consecutive patients who underwent adjuvant chemoradiation in our institution in the years 2006-2009. 45Gy in 5 weeks with concurrent two cycles of FUFA Mayo regimen chemotherapy were administrated as part of combined treatment. The acute toxicity was relatively mild (CTCAE scale): grade 2 nausea in 26%, vomiting in 13%, and diarrhoea grade 1 in 15% and general abdominal discomfort in 57% of patients. Grade 3 haematological and infectious complications in 6% and 2% respectively. Late adverse events were as follows: grade 1 esophageal toxicity in 17%, signs of mild chronic esophageal ulceration and esophageal stenosis in 9% of patients (50% of them had tracheoesophageal fistula). The Kaplan- Meier estimate of the median overall survival was 30.5 months with median 25.7 months disease free survival. The overall survival was statistically significantly affected by the amount of removed positive lymph nodes. For the proper evaluation of radiotherapy role in multimodal treatment approach, results of other clinical trials investigating role of concurrent radiotherapy in administration of perioperative chemotherapy will be necessary. Meanwhile, two equally approaches are possible, all having their pros and cons. Institutional toxicity evaluation is recommended in order to provide the best care possible. Keywords: adjuvant chemoradiation, gastric cancer, early toxicity, late toxicity, survival outcomes.

Helicobacter pylori and gastrointestinal symptoms in diagnostics and adjuvant chemotherapy of colorectal cancer

5-Fluorouracil (5-FU)-based chemotherapy is the mainstay of adjuvant treatment for colorectal cancer (CRC). Few studies have explored Helicobacter pylori (H. pylori)-associated gastrointestinal symptoms in the diagnosis of CRC, and the association between H. pylori infection and gastrointestinal toxicity during adjuvant chemotherapy in CRC. Seventy-nine CRC patients were randomised in a prospective clinical trial to receive 5-FU and leucovorin administered as bolus injection (Mayo regimen) or continuous infusion (simplified de Gramont regimen). H. pylori antibodies were analysed at baseline, twice monthly during treatment and after treatment up to 12 months. Thirty-seven patients (47%) were H. pylori-seronegative at baseline. There was no significant association between baseline H. pylori seropositivity (n=42; 53%) and oro-gastrointestinal toxicity during chemotherapy. The median time from symptom onset of CRC to surgery was significantly longer in patients with H. pylori infection (median time, 6 vs. 5 months; P=0.012). Functional dyspeptic symptoms at presentation significantly delayed diagnosis (median time, 7.5 vs. 5 months; P=0.035), whereas anaemia, bowel symptoms, occlusion, blood in the stool, infection and hypolactasia did not. We conclude that there is no association between H. pylori status and gastrointestinal toxicity in CRC patients during chemotherapy. Dyspeptic symptoms and presence of H. pylori may delay the diagnosis of CRC. (www.controlled-trials.com/ISRCTN98405441).

5‐Fluorouracil‐based chemotherapy for colorectal cancer and MTHFR/MTRR genotypes

5‐Fluorouracil‐based chemotherapy for colorectal cancer and <i>MTHFR</i>/<i>MTRR</i> genotypes

Comparative Analysis of Dose Distribution and Acute Toxicity with Intensity Modulated Radiation Therapy (IMRT) vs. Conventional Radiation Therapy in Gastric Carcinoma

In the past decade, major change in the management of gastric carcinoma was brought about by the results of the Gastrointestinal Intergroup Trial that incorporated the role of adjuvant chemoradiation but at the expense of increased hematological and gastrointestinal toxicity. The aim of this study was to assess the efficacy of IMRT in reducing this toxicity. This is a retrospective analysis of 30 patients of gastric carcinoma (T3-4\N+) who received adjuvant chemoradiation at our institute. Most patients underwent radical total gastrectomy with D2 resection and received chemotherapy by the Mayo's regimen. Among these 15 patients underwent IMRT, and the other 15 received conventional radiation. Conventional radiation was done using three fields (Anterior and two wedged lateral pairs) to a dose of 45-50Gy in 25-28 fractions over 4.5-5 weeks. IMRT was delivered using 5-7 co-planar beams. The clinical target volume (CTV) encompassed the gastric bed, perigastric extension & the draining lymph nodes. Diagnostic scans, surgical clips and endoscopy findings guided CTV delineation. Planning target volume (PTV) was created with 1cm expansion in axial planes and 1.5-1.8 cm in craniocaudal direction, as per the diaphragmatic excursion. Dose of 45-50 Gy was prescribed to the 95% of the volume of CTV. Dosimetric comparison was done using DVH of both the groups. The mean doses received by the 33%, 50% and 66% of the volumes of organs at risk (OAR) were compared by the independent sample t - test. The clinical data was reviewed for the acute toxicities, which were graded according to the CTC version 3.0. IMRT reduced the mean doses to all the OAR's (kidneys, liver, small bowel & spinal cord) but it was statistically significant only for the small bowel, liver and spinal cord. Mean doses received by 50% of small bowel was 28.52Gy and 42.08Gy for IMRT and conventional radiation therapy groups respectively (p = 0.00). The corresponding doses for the liver were 18.04Gy and 31.88Gy respectively (p = 0.01). The Dmax to the spinal cord in both the groups were 30.61Gy and 45.04Gy respectively (p = 0.00). Acute toxicities were higher in the patients who underwent conventional radiation, with 11 (73 %) patients experiencing grade 2-3 gastrointestinal toxicity and 5 (33%) hematological toxicity. In the IMRT group, 2 patients (13%) had grade 2 gastrointestinal toxicity and 4 (26%) had grade 2 hematological toxicity. There was a significant reduction in the radiation doses to the OAR's with IMRT, which was reflected in the lesser acute toxicities seen in that group. This encouraging correlation can improve the tolerance of patients to chemoradiation which in turn can translate into better locoregional control and survival.

Colorectal cancer survival following adjuvant chemotherapy with weekly i.v. fluorouracil 425 mg/m2 and folinic acid 50mg

e15089 Background: Adjuvant chemotherapy for colorectal cancer (CRC) using fluorouracil (5FU) and folinic acid (FA) has been proven effective and the QUASAR trial showed that a weekly administration schedule was as effective as, and less toxic than, the same daily doses delivered over 5 days every 4 weeks (the “Mayo regimen”). However the 5FU dose used (370 mg/m2) was lower than in some trials and a higher 5FU dose was considered desirable if tolerated. We therefore implemented a weekly regimen using 5FU 425 mg/m2 and DL-folinic acid 50mg in 2001 and retrospectively evaluated its efficacy and tolerability. Methods: Patients with non-metastatic CRC at assessment by medical oncologists in this institution between 2001 and 2004 were included in the analysis. Data was gathered on patient characteristics, duration of adjuvant chemotherapy and survival. Actuarial survival was calculated using the Kaplan-Meier method. Results: 417 patients (pts) were seen: 181 females, 236 males; median age 67 yrs (24–89); 291 with colon cancer, 126 with rectal cancer; 1 stage 1; 100 stage 2, 316 stage 3. Median follow-up was 6.2 years. 210 pts with colon cancer received adjuvant weekly 5FU/FA (32 stage 2, 178 stage 3) as did 58 pts with rectal cancer (50 of whom also received concurrent chemoradiation). 75% of pts with colon cancer received all 30 planned doses and 59% of rectal cancer pts received all 20 planned doses. 3 year survival for all pts treated with this regimen was 83.0% and for the subgroups with colon and rectal cancer it was 82.4% and 84.5% respectively. For stage 2 and 3 colon cancer pts treated with this regimen 3 year survival was 87.9% and 76.0% respectively; for stage III rectal cancer pts it was 84.1%. Conclusions: These outcomes compare favorably on indirect comparison with results from the QUASAR trial (which reported 3 year survival of 70.6%) and suggest that using a higher 5FU dose in this regimen is tolerable and may be advantageous. No significant financial relationships to disclose.

Oxaliplatin-Mediated Autoimmune Thrombocytopenia

Drug-induced immune thrombocytopenia (DITP) has been associated with > 100 drugs, including chemotherapeutic agents. Platelet destruction in DITP is caused by immunoglobulins that recognize specific platelet membrane glycoproteins only in the presence of the sensitizing drug.1,2 The diagnosis of DITP is often delayed in patients with cancer who develop thrombocytopenia after the administration of chemotherapeutic agents and is most commonly attributable to myelosuppression by chemotherapy and/or marrow replacement by the tumor. We previously described a case of thrombocytopenia caused by oxaliplatin,3 and in this report, we describe another patient who developed severe thrombocytopenia and bleeding symptoms during treatment of metastatic colon cancer with oxaliplatin. A 57-year-old black woman with stage IV colon cancer was transferred from a local hospital with bleeding from her port in the setting of profound thrombocytopenia. Her past treatments included 6 cycles of systemic 5-fluorouracil (5-FU) and leucovorin per the Mayo Regimen that was subsequently changed to XELOX-B (oxaliplatin; 130 mg/m2 day 1 every 3 weeks, capecitabine 850 mg/m2 orally twice daily × 14 days, bevacizumab 7.5 mg/kg every 3 weeks) because of progressive disease. The patient received her 11 cycles of XELOX-B about 17 hours before the onset of bleeding. The hematologic profile before initiating the eleventh cycle showed the following: white blood cell count: 2.3/mm3 (absolute neutrophil count: 1.8/mm3); hematocrit (HCT): 40%; and platelet count: 89 × 109/L. On presentation, the patient was afebrile and hemodynamically stable. A slow but continuous bleeding was noted at the site of her porta-catheter on the right side of her chest with no local evidence for trauma or infection. Laboratory data demonstrated a platelet count of 17 × 109/L. The patient was transfused with 6 units of platelets and transferred to the university hospital for further management. After transfer, further laboratory work was obtained, which showed platelet count of 27 × 109/L. Disseminated intravascular coagulation (DIC) panel was negative for any abnormality, and HCT dropped to 29%. The patient was observed in the hospital, and her platelet count was checked every 12 hours as shown in Figure 1. Because of concern for oxaliplatin-mediated autoimmune thrombocytopenia, serum was collected on the third day of hospitalization and sent to the Blood Center of Southeastern Wisconsin, Inc. to detect drug-dependent antibodies. Drug-dependent platelet antibodies were detected in patient sera using flow cytometry as previously described.4-6 In brief, normal group O platelets were incubated with test serum in the presence and absence of drug and were washed twice in buffer containing drug at the same concentration as in the primary incubation mixture. Platelet-associated immunoglobulins were then detected by flow cytometry using fluorescein isothiocyanate (FITC)–tagged anti-human immunoglobulin (Ig) G (Fcγ-specific) and phycoerythrin (PE)-tagged anti-human IgM, (Fcμ-specific). Sera from normal, healthy donors and sera containing previously identified quinine-dependent platelet antibodies served as negative and positive controls, respectively. In selected studies, platelets were “coated” with oxaliplatin by incubating washed normal platelets with the drug at various concentrations followed by 5 washes in 1.5-mL volumes of acid citrate dextrose (ACD)/phosphate-buffered saline (PBS)/bovine serum albumin (BSA) to remove unbound drug. A positive reaction was defined as mean platelet fluorescence intensity (MFI) at least twice that of platelets processed identically except for the absence of drug. Reactions of this strength always exceeded

Is Fluorouracil-Induced Severe Toxicity in DPYD*2A Individuals Related to Sex or to Treatment Regimen?

TO THEEDITOR:We very much appreciate the prospective manner of the study conducted by Schwab et al, 1 in which fluorouracil (FU) treatment-related toxicity was correlated with genetic and nongenetic factors in patients treated with FU monotherapy-based regimens. The study elegantly illustrated the complex and diverse clinical pictureallelicvariantsmayinduce,andservesasamodelforprospective pharmacogenetic validation studies. However, we propose that theauthorstakeanotherpotentiallycrucialparameterintheiranalysis into account that might lead to a different interpretation of the study results. Toxicity to FU depends on the type of treatment regimen, also illustrated by Schwab et al, with the bolus Mayo regimen resulting in the highest overall grade 3/4 toxicity rate. Based on the study results presented,webelievethatdevelopmentofseveretoxicityinDPYD*2A heterozygotes is determined by the treatment regimen and not by mode of administration nor by sex. Schwabetalobservedthatonlysixoutof13DPYD*2Aheterozy

Epidermal growth factor expression affects clinical outcome in colorectal cancer

15125 Background: To elucidate the level of ECFR expression in colorectal cancer and the impact of chemotherapy on survival according to this expression. Methods: 50 patients with CRC staged II and III (AJCC). Group I (20) cases with negative expression subjected to adjuvant chemotherapy Mayo clinic regimen. Group II with expressed EGFR (30) case sub classified to 2 subgroups (A) (17 cases) received Mayo Clinic regimen and subgroup (B) (13 cases) received intensive protocol (FOLFOX or FOLFIRI). Both groups were well balanced. Results: Table (1). Conclusions: 1- EGFR expressed in 60% of our cases 2- RFS was significantly higher in group I with -ve expression versus +ve expression. 3- OAS was higher in group I with -ve expression versus + ve expression but this increase didn't reach statistical significance. 4- In those subsets of patients with expressed EGFR the mean value of survival was better in the group received intensive chemotherapy than those received conventional protocol (Mayo regimen) although the difference didn't reach statistical significance. Patient Characteristics NO % No 50 . Mean age y. 45 . Male 19 38 Female 31 62 EGFR +ve 30 60 EGFR −ve 20 40 Stage II 26 52 Stage III 24 48 Histology: Adenocarcinoma Histology: 38 72 Mucinous Histology: 11 22 Signet Ring 1 2 No significant financial relationships to disclose.

Potential budget impact of capecitabine versus 5-FU/LV as adjuvant chemotherapy for stage III (SIII) colon cancer in Canada and its provinces

6581 Background: Adjuvant chemotherapy for SIII colon cancer is an accepted standard of care. Oral Capecitabine (CAP) has been shown to be at least equivalent and possibly superior to 5FU/LV (Mayo regimen) with regards to a superior relapse free survival. This new option is associated with a higher drug cost but improved toxicity profile and appears to be cost-effective (CE). An economic analysis was undertaken to examine the potential budget impact for CAP in Canada and its provinces for 2007 onwards. Methods: A previously developed cost-effectiveness model was adapted to a prevalence perspective to project the net budgetary impact of CAP over a 5 year horizon. The projected population and incidence of colon cancer for each Canadian province from 2007–2016 was obtained and the proportion of patients with SIII colon cancer suitable for adjuvant chemotherapy was estimated from the literature. The average budget impact in the first 5 years (start up phase) and subsequent years (steady state) was assessed in Canadian $. Results: The projected average annual impact for Canada is 13.9 million (M) during the start up phase and $11.8 M during the steady state phase (NL $210K, PEI $63K, NS $424K, NB $282K, QC $2.92M, ON $4.66M, MB $464K, SK $336K, AB $993K and BC 1.45M). Budget impact is greater during the initial start-up phase (2007–11), as the steady state impact (2012–16) includes relapses avoided over a 5-year period. Sensitivity analyses for key parameters will be provided. Conclusions: The annual budget impact of CAP decreases over time and reaches a steady state after 5 years when the full impact of decreased recurrences is captured. As CAP appears to be CE, budget impact analysis has the potential to assist in the planning of healthcare funding resources regarding this treatment option. [Table: see text]

Patient preference for oral or intravenous chemotherapy: A randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer

Until recently, flourouracil ( F ) and leucovorin ( L ) had been considered the standard therapy for patients with colorectal cancer. However, several studies have shown that oral therapy with UFT/L or capecitabine is as effective as intravenous (i.v.) therapy and in addition it is claimed that patients prefer oral to i.v. therapy as long as efficacy is not compromised. In a previous crossover study by Borner et al., it was shown that 26 out of 31 patients preferred oral therapy with UFT/L to i.v. FL (Mayo regimen) [Borner M, Schöffski P, de Wit R, et al. Patient preferences and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002; 38:349–58]. The objective of the present study was to investigate patient preference between i.v. FL and oral capecitabine using the design described by Borner. The Nordic FL schedule is a bolus regimen with efficacy comparable to other i.v. regimens and at the same time a very tolerable and easy administered regimen. We randomised 60 patients with colorectal cancer (53 patients received adjuvant therapy and seven patients received palliative therapy) to start therapy with either oral capecitabine or Nordic bolus FL. After 6 weeks of therapy (two courses of capecitabine or three courses of Nordic FL) patients were crossed over to the other regimen. After having completed 12 weeks of therapy the patients (49 evaluable patients) were asked to choose one of the regimens for a further 12 weeks of therapy. Patients had more side-effect when treated with capecitabine and a total of 30 out of 49 (61%) preferred the Nordic FL regimen and 19 (39%) preferred capecitabine. We conclude that patients prefer the regimen with less toxicity and that it is of minor importance whether the medication is administrated orally at home or i.v. at the hospital.

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G&gt;A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]

Tolerability of fluoropyrimidines appears to differ by region

3514 Background: Limited information is available regarding regional differences in tolerability for fluoropyrimidines. This is an initial assessment of the Roche phase III databases on patients treated for metastatic colorectal cancer (MCRC) and adjuvant colon cancer. Methods: Retrospective multivariate analyses (logistic regression) were performed using pooled data from two identical studies (n=1189) in MCRC comparing capecitabine (X) monotherapy with i.v. 5-FU/LV (Mayo regimen) [Hoff et al. and Van Cutsem et al. JCO 2001], and from an adjuvant study (n=1861) comparing XELOX (X+oxaliplatin) with either the Mayo or Roswell Park 5-FU/LV regimens [Schmoll et al. ASCO 2005]. Treatment-related safety parameters evaluated were: all grade 3/4 AEs, grade 3/4 GI events (diarrhea, nausea, vomiting, stomatitis), and grade 3/4 neutropenia events (febrile neutropenia, neutropenia reported as AE or lab value). Dependent variables for 1st-line MCRC data were: US vs. non-US; and for adjuvant colon cancer: US vs. non-US, US vs. Asia, and RoW (rest of the world) vs. Asia. Factors in the adjusted relative risk model were: age, gender, PS, BSA, BMI, baseline creatinine clearance and treatment (X vs. 5-FU/LV; XELOX vs. Mayo vs. RP). Results: Region was significantly associated with grade 3/4 AEs and grade 3/4 GI events in both settings ( table ). There were no relevant interactions between region and type of fluoropyrimidine treatment. Reporting of grade 3/4 neurosensory toxicity was similar in the US and outside US. Conclusions: Differences in the rates of grade 3/4 toxicity were significantly associated with the region of the world in which the patients were treated. Patients treated in the US experienced the highest rates of grade 3/4 toxicity (see table ). This difference was observed for both X and for 5-FU. The reasons for these differences remain to be elucidated. Acknowledgements: C. Allegra, J. Bertino, J-Y Douillard, B. Gustavsson, G. Milano, M. O’Connell, Y. Rustum, J. Tabernero, J. Fagerberg, F. Gilberg, and F. Sirzen. [Table: see text] [Table: see text]

Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study

3563 Background: Patients with stage III colon cancer have a high risk for recurrence. Infusional 5-FU may be more active than bolus application. Methods: From 01/1997 to 03/2004 a total of 1601 patients with UICC stage III colon cancer were randomized to receive the Mayo-Clinic regimen or infusional 5-FU either the weekly high dose AIO regimen, the bi-weekly LV5FU2 regimen or the Spanish weekly high dose TTD-regime. The major aim of this study was to demonstrate a difference of 7 % in the 5 year survival rate in favour of the infusional arm for which a total of 424 events were required. Results: After a median follow-up of 31 months 478 events have occurred. 804 patients received the standard arm and 797 the experimental arm (AIO N=331, EORTC N=92, FFCD N=211, TTD N=163). The median age was 64 years; patients were well distributed according to TNM-category (T3 73 vs. 75%, T4 17 vs. 16%, N2 31 vs. 34%), vascular and lymphatic invasion and grading. The bolus regimen induced a higher rate of grade 3 or 4 leukopenia (7.1% versus 2.0%), stomatitis grade 3 or 4 (9.8% versus 3.3%) or diarrhea grade 3 or 4 (16% vs. 15%). Hand-Foot-Syndrome was more frequent in the experimental arm (4.4% versus 0.4%). There was no difference in the recurrence free survival at 5 years (57% versus 56%; hazard ratio 1.00, 95% CI, 0.84 to 1.21; P=0.9) or overall survival at 5 years 71% versus 72%; hazard ratio 0.91, 95% CI, 0.71 to 1.16; P=0.44). Conclusions: Infusional 5-FU does not improve RFS or overall survival of stage III colon cancer compared to the Mayo regimen but is less toxic. Supported by Deutsche Krebshilfe No significant financial relationships to disclose.

Adjuvant Chemotherapy in Elderly Patients (≥75 yr) Completely Resected for Colon Cancer Stage III Compared to Younger Patients: Toxicity and Prognosis

To compare benefits and risks to adjuvant chemotherapy following complete resection of node-positive colon cancer stage III for patients aged >or=75 yr and younger. A retrospective study compared recurrence-free and overall survival, toxicity, and dose intensity of adjuvant bolus 5-FU according to the Mayo regimen chemotherapy in consecutive patients aged 19-74 (n=203) and >or=75 yr (n=24). The estimated 5-yr proportional survival rates were 0.65 for patients age less than 75 yr compared to 0.65 (p=0.96) for elderly. The frequencies of anemia (0%), thrombocytopenia (0%), leukopenia (4%), infection (8%), vomiting (0%), mucositis (17%), diarrhea (13%) CTC grade 3 or 4 toxicity in elderly patients were not significantly different from that in younger patients (p > 0.05). Significantly more elderly (8%) had a decline in performance status to grade 3 or 4, as compared to younger patients (4%) (p=0.002). 5-FU dose reduction was necessary for significantly more elderly (51%) as compared to younger patients (28%) (p=0.02), and fewer elderly (54%) completed the scheduled six treatment courses as compared to younger patients (82%) (p=0.05). Adjuvant 5-FU chemotherapy should be considered for elderly patients aged >or=75 yr in good performance at high risk of recurrence of colon carcinoma after resection.

Who should be considered for FOLFOX adjuvant chemotherapy? An analysis of Dukes B colorectal cancer in a Royal Marsden Hospital randomized trial

3559 Background: Based on the positive results of adjuvant fluoropyrimidine chemotherapy in Dukes B colorectal cancer in the QUASAR trial it is expected that more patients with this stage of disease will be offered chemotherapy. Furthermore the MOSAIC study has indicated a role for combination chemotherapy with FOLFOX in these patients. Thus we have conducted an analysis of the disease-free and overall survivals (DFS and OS) of the Dukes B patients from our multicentre randomized trial which compared two 5-FU based regimens (Mayo regimen versus protracted venous infusion) to determine the influence of other adverse clinical and histological prognostic factors on outcome. Methods: Patients were considered high risk if ≥1 of the following was present: poorly differentiated or mucinous tumours; T4 stage; extramural venous invasion; presentation with either perforation or obstruction. Results: Between 1993 and 2003, a total of 801 patients received treatment within the study. Of these, there were 277 Dukes B patients from RMH who were high (n=94) or low (n=183) risk. The proportion of patients from both treatment arms in both groups was well matched. The median follow-up at the time of analysis was 6.2 years. There have been 53 relapses and 58 deaths in the patient cohort to date.The 3-year DFS for the high and low risk groups was 70.9% [95% CI: 60.5–79.0%] and 87.9% [95% CI: 82.2–91.9%] respectively (HR=1.85 [95% CI: 1.13–3.04; p=0.0078]).The 5-year OS for the high and low risk groups was 77.6% [95% CI: 67.5–85.0%] and 86.7% [95% CI: 80.6–90.9%] respectively (HR=1.69 [95% CI: 0.97–2.96; p=0.0474]). In comparison, the 5-year OS for the entire group of Dukes C patients entered in the study was 67.3% [95%CI: 62.4–71.7%] respectively. Conclusions: Patients with Dukes B colorectal cancer who had at least one adverse prognostic feature, who received adjuvant chemotherapy with 5-FU alone, had a significantly worse OS (5-year OS 77.6% versus 86.7%) and DFS compared to those who did not have any such factors. This reinforces the case for adjuvant chemotherapy with FOLFOX in this group of patients. No significant financial relationships to disclose.

Lactose intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer

Background & Aims: Bowel mucosal injury associated with 5-fluorouracil (5-FU) treatment might result in secondary lactose intolerance. The frequency and clinical significance of 5-FU-related hypolactasia are unknown. Methods: One hundred fifty patients randomly assigned to receive 1 of 2 adjuvant 5-FU-based chemotherapy regimens, the Mayo regimen or the simplified de Gramont regimen, were studied for lactose tolerance by using an oral lactose absorption test, a symptom questionnaire, treatment-related toxicity, and Subjective Global Assessment of Nutritional Status questionnaire before, during, and 2 and 6 months after chemotherapy for colorectal cancer. Results: The frequency of hypolactasia increased from 24% before treatment to 35% during treatment ( P < 0.0001). Therapy-related hypolactasia was reversible on discontinuation of chemotherapy. Symptoms compatible with lactose intolerance occurred in 94% of patients with an abnormal lactose absorption test result during chemotherapy. The frequency of hypolactasia increased during chemotherapy in both treatment groups, but was detected more commonly in those for whom therapy included continuous 5-FU infusions (the de Gramont regimen; 45% vs. 25%; P = 0.006). The presence of hypolactasia during chemotherapy was associated with flatulence, diarrhea, and poor nutritional status. Conclusions: Reversible chemotherapy-related hypolactasia and lactose intolerance are not infrequent in patients treated with 5-FU-based adjuvant chemotherapy for colorectal cancer. Avoidance of lactose during chemotherapy may improve treatment tolerability in these patients.

5-FU plus leucovorin (Mayo Regimen) for concurrent chemoradiotherapy after surgery in patients with resectable locally advanced gastric carcinoma: Preliminary results of a phase II study

4196 Background: Patients with locoregionally advanced carcinoma of the stomach have a grim outcome due to frequent local and systemic recurrences after surgery. To potentially increase the local control or survival rate and decrease relapses, we investigated a strategy of concurrent chemoradiotherapy and followed by consolidation chemotherapy after surgery. Methods: Operable 71 patients (Stage IB-IV, M0) underwent total or subtotal gastrectomy. Adjuvant chemotherapy (250 mg/m2 5-FU) was administered concurrently on the first day of every radiotherapy weeks [which was totally standart field radiotherapy (RT), or total abdominal field RT up to 20 Gy first, then returned to standart field RT], . After chemoradiotherapy regimen, consolidation chemotherapy consisted of 450 mg/mg 5-FU plus 20 mg/m2 Leucovorin was applied up to four cycles, q28 d. Results: Of 71 patients have been enrolled, 67 (94%) of 37 (55%) were randomized to standart field RT arm, and 30 (45%) were randomized to total abdominal irradiation arm. There were not significant difference between two arms according to the age, sex, surgical approach, tumor localization, and stages. Six patients in both arms did not get consolidation chemotherapy. The median follow-up was 7.5 months (range: 6–29 m). One-year progression-free survival was 53% and 65% on the first and second arm, respectively. The overall survival was 63% and 70% on the first and second arm, respectively. Nine patients (24%) on the first, and 12 (40%), and on the second arm were died. There was not a significant difference between the two groups. Commonest side effects during chemoradiotherapy were grade 3–4 neutropenia on the first arm (14%), diarrhea on the second arm (17%). There were no deaths related to chemotherapy, chemoradiotherapy, or surgery. Conclusions: Preliminary results suggest the feasibility of postoperative adjuvant chemoradiotherapy with 5-FU followed by consolidation chomotherapy with MAYO regimen in gastric cancer with acceptable toxicities. No significant financial relationships to disclose.