Use of the folinic acid/5-fluorouracil/irinotecan (FOLFIRI 1) regimen in elderly patients as a first-line treatment for metastatic colorectal cancer: a Phase II study

Background  The aim of this study was to evaluate the effects of a combination of folinic acid, 5-fluorouracil (5FU) and irinotecan (FOLFIRI 1) administered every 2 weeks in a population of elderly subjects with advanced colorectal cancer. Patients and methods  Patients with metastatic colorectal cancer included in this study were aged at least 70 years, with a performance status of 0/1, without geriatric syndrome and without previous palliative chemotherapy. They received irinotecan [180 mg/m² intravenous (iv) infusion over 90 min] followed by folinic acid (400 mg/m² iv over 2 h), then 5FU (400 mg/m² iv bolus) and 5FU (2,400 mg/m² continuous iv infusion for 46 h) every 2 weeks. Results  Forty eligible patients were included. The median age was 77.3 years (range 70–84.7). The objective response rate was 40% and the stabilisation rate was 45%. Median progression-free survival was 8 months, overall survival was 17.2 months and cancer-related specific survival was 20.2 months. In total, 300 cycles of chemotherapy were administered with a median number of eight cycles per patient (range 1–18). Tolerance was good; grade 3/4 toxicities included diarrhoea (15%), asthenia (15%), nausea/vomiting (7.5%) and neutropenia (7.5%). One toxic death was observed due to grade 4 diarrhoea. Conclusion  The FOLFIRI 1 regimen is a valid therapeutic option for elderly patients in good clinical condition. This study was partly sponsored by Pfizer, Paris, France.     

Anemia is the strongest prognostic factor for outcomes of 5-fluorouracil-based first-line chemotherapy in patients with advanced gastric cancer

Objective: To examine the prevalence of anemia and its impact of hemoglobin (Hgb) levels in predicting outcomes of 5-fluorouracil (FU)-based first-line chemotherapy for patients with advanced gastric cancer (AGC). Methods: We collected data retrospectively from 511 consecutive patients treated with FU-based first-line chemotherapy as a routine clinical practice for AGC and followed up in two centers from 1995 to 2003. FU was given in combination with cisplatin (61%), taxanes (12%), anthracyclines (24%) and/or folinic acid (50%). Results: Hgb values were <10 g/dl in 41%, and patients with baseline Hgb levels <10 g/dl had significantly lower response rates (9%) than patients with Hgb≥10 g/dl (53%; P<0.001). In addition, Hgb<10 g/dl served as a predictor for disease progression (RR, 1.77; 95% CI, 1.42–2.21) and death (RR, 1.85; 95% CI, 1.48–2.32) along with chemotherapy response and performance status. Conclusion: Low baseline Hgb level is a strong and independent prognostic factor for the outcomes of AGC patients receiving FU-based first-line chemotherapy. This results strongly suggest that Hgb level, along with performance status, may be considered as a stratification variable in subsequent studies of AGC.     

Effects on DNA and RNA after the administration of two different schedules of 5-fluorouracil in colorectal cancer patients

Purpose 5-Fluorouracil (5-FU) has two major mechanisms by which it exerts its anticancer activity. One mechanism operates through the inhibition of thymidylate synthetase (TS) by the active metabolite 5-fluorodeoxyuridine 5-monophosphate. The other mechanism is the incorporation of 5-FU into RNA. Using tumor tissue specimens from colon carcinoma patients given 5-FU by two different modes of administration, we investigated the effects of 5-FU on DNA and RNA.Experimental design Group A patients received 200 mg/day of 5-FU as a rapid infusion for 5 days preoperatively, and group B patients received 200 mg/day of 5-FU as a continuous infusion for 5 days preoperatively. Postoperatively, we analyzed the 5-FU concentration, 5-FU incorporation into RNA (F-RNA), and TS inhibition rate (TSIR) in normal tissue, cancerous tissue, and lymph nodes.Results The F-RNA concentration in tumor tissue from group A patients was higher than in tissue from group B patients. The TS concentrations in tumor tissue were significantly higher than in non-tumor tissue in both groups. In lymph nodes, the TSIR of group A was 78.5% and that of group B was 55.2%, a significant difference.Conclusion Bolus injection can be considered to be more effective with respect to RNA damage in tumor tissue. Especially in cases involving lymph node metastasis, bolus injection was effective with respect to DNA damage as well as RNA damage.     

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer

Purpose: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. Methods: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m²) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m²) and then continuous infusion (600 mg/m²) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. Results: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL _mean ) and initial volume of distribution (V), were as follows: the male subgroup showed a CL _mean value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. Conclusion: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients. Received: 21 September 1998 / Accepted: 20 January 1999     

Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracilresponsive subgroup?

The CpG island methylator phenotype (CIMP+) of colorectal cancer (CRC) occurs predominantly in the proximal colon and is characterized by frequent hypermethylation of gene promoter regions. In this review, we present evidence suggesting CIMP+ represents the subgroup of colon cancers that are responsive to 5-fluorouracil (5-FU)-based treatments. CIMP+ has been associated with survival benefit from 5-FU in a clinical study of CRC, with additional evidence coming from studies on gastric cancer and tumor cell lines. Elevated concentrations of 5-10-methylene tetrahydrofolate (CH₂FH₄) occur in CIMP+ tumors and are probably due to low expression levels for γ-glutamyl hydrolase (GGH). Clinical and in vitro work has previously shown that high CH₂FH₄ and low GGH expression levels correlate with good response to 5-FU. Methylation-induced silencing of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU degradation, may also provide a link between CIMP+ and good response to 5-FU. The CIMP+-related phenotype referred to as microsatellite instability (MSI+) has been widely investigated as a predictive marker of response to 5-FU, with contradictory results. The interpretation of these studies is likely to be confounded by the fact that some MSI+ tumors occur in the background of CIMP+, but a significant proportion of others do not. Further studies on tumors from randomized clinical trials are required to confirm the value of CIMP+ and associated molecular features for the prediction of clinical outcome to 5-FU-based chemotherapy.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.     

Synergistic antitumor effect of 5-fluorouracil in combination with parthenolide in human colorectal cancer

Parthenolide (PT), a NF-κB inhibitor, has recently been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. 5-fluorouracil (5-FU) has been a drug of choice for treatment of colorectal cancer (CRC). Unfortunately, many of the therapies that use 5-FU alone or in combination with other agents are likely to become ineffective due to drug resistance. In the present study, we investigated the antitumor effect of PT combined with 5-FU on a human CRC cell line, SW620. The results demonstrated that combination of PT and 5-FU induced apoptosis which was determined using MTT, cell cycle analysis, annexin-V assay, and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome C release, and activation of caspase 3 and 9. Moreover, intra-peritoneal injection of PT and 5-FU showed significant inhibition of tumor growth in the xenograft model. These results demonstrate that PT exhibits anticancer activity in human colorectal cancer in vitro and in vivo. These findings provide an efficacious strategy to overcome 5-FU resistance in certain CRC.     

5-Fluorouracil and low-dose leucovorin in metastatic colorectal cancer: a pilot study

 A total of 56 consecutive patients with metastatic colorectal cancer received treatment with 5-fluorouracil (5-FU) given at 425 mg/m² by rapid intravenous infusion, immediately preceded by leucovorin (LV) given at 20 mg/m², with cycles being repeated every 4 weeks. Of 48 evaluable patients undergoing this treatment, a tumor response was observed in 16 (33%); a complete response, in 2 (4%); and a partial response, in 14 (29%). The median survival was 8.5 months for all patients and 16.5 months for responders. An improvement in symptoms was seen in 9 (26%) of 34 symptomatic patients. In all 15 (27%) of 44 evaluable patients showed an improvement in performance status. The most significant toxicity attributable to the treatment was mucositis of grade 3 or 4, seen in 27% of the patients. Altogether, 2 patients (3.5%) were hospitalized for treatment-related toxicity. We conclude that the combination of 5-FU and low-dose LV is active in advanced colorectal cancer and is associated with acceptable toxicity. Received: 9 May 1994/Accepted: 15 July 1994     

Treatment of colorectal cancer in the elderly: a review of the literature

Although major progress has been achieved in the treatment of colorectal cancer, there are still several questions open for discussion concerning the management of elderly colorectal cancer patients. We conducted a review of the available literature concerning the use of adjuvant chemotherapy, palliative chemotherapy and surgery in elderly patients with colorectal cancer, using data from meta-analyses, non-systematic reviews and individual trials. All report similar survival benefits with adjuvant and palliative chemotherapy in elderly patients in comparison with younger age groups. Data on treatment-related side effects did not reveal a different toxicity profile for elderly patients. Efficacy and safety data were similar but more difficult to interpret concerning surgery, so this review is inconclusive about the proper use of this treatment modality in the elderly population. It is demonstrated that there is significant gain from chemotherapy in the adjuvant and palliative management of colorectal cancer patients irrespective of age. We, therefore, conclude that all patients should receive the most intensive treatment thought to be effective and safe, according to their biological age and comorbidities.     

Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial)

BackgroundChemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers.MethodsWe conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1–28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety.ResultsFrom October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9 months, the median OS was 25.0 months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%).ConclusionOur results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC.     

Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials.

BACKGROUND: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according to the standard therapy. Although there is evidence that elderly patients benefit from adjuvant (radio-) chemotherapy to the same extent as younger patients, no large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a retrospective analysis using source data of 3825 patients who received 5-fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of > or = 70 years. RESULTS: We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (CI) 9.7-11.8] and in younger patients (11.3 months, 95% CI 10.9-11.7; P = 0.31). Response rate did not differ between age groups > or = 70 and <70 years (23.9% and 21.1%; respectively; P = 0.14). Progression-free survival was marginally prolonged in elderly patients (5.5 months, 95% CI 5.2-5.8; compared with 5.3 months, 95% CI 5.1-5.5; P = 0.01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression-free survival compared with bolus 5-FU. CONCLUSIONS: 'Fit' elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.     

Palliative 5-fluorouracil-based chemotherapy for advanced colorectal cancer in the elderly: results of a 10-year experience

The aim of this study was to evaluate the objective tumor response rates and toxicities in elderly patients (older than 70 years) with advanced colorectal cancer treated with 5-fluorouracil (5-FU) as a first-line palliative chemotherapy regimen. Eighty-six consecutive patients were enrolled onto a retrospective study between January 1990 and February 1998. Patients were divided into two groups; group 1 consisted of patients who were 70 to 74 years old, and group 2 consisted of patients who were age 75 years and older. Four types of 5-FU-based chemotherapy were administered. First-line chemotherapy was continued until disease progression, unacceptable toxicity, or patient refusal. Primary tumor sites were the colon (n = 44), rectum (n = 29), and colorectal (n = 13). There was no difference in response (complete/partial) rates according to age groups (group 1: 21%, group 2: 26%). Median overall survival was 17 months for group 1 and 14 months for group 2, with 1-year survival at 63% and 55%, respectively (not statistically significant). Median time to progression was 6 months for both age groups. Chemotherapy in both groups increased performance status, and weight in 26% and 31%, respectively. No toxic death was reported. There was no difference in overall or severe toxicity between the two age groups, and all adverse events were manageable. Toxicity (grade III/IV) occurred in 25% of patients. Based on these findings, palliative first-line chemotherapy for colorectal cancer can be performed in selected elderly patients without increasing either morbidity or mortality, while obtaining response rates and side effects comparable to those in younger patients.     

草酸铂为主联合化疗方案治疗晚期大肠癌的临床观察

目的 观察草酸铂(OXA)联合醛氢叶酸(CF)，5-氟脲嘧啶(5-Fu)治疗晚期大肠癌的近期疗效及毒副反应。方法 OXA130mg／m^2，iv drip dl；CF100mg，iv dl-5；5-Fu375mg／m^2，iv dl-5。以上方案每21天为一周期，至少完成二周期。结果 CR1例，PR8例，SD9例，PD7例。总有效率36．0％，主要毒副反应为恶心呕吐和血白细胞减少，外周神经感觉异常。结论 草酸铂为主联合化疗方案治疗晚期大肠癌疗效较好，毒副反应可耐受，值得临床推广应用。     

A clinical and pharmacological study of 5-fluorouracil,leucovorin and interferon alfa in advanced colorectal caner

Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon. Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m² plus LV 20 mg/m² daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m² subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0–40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P<0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.This work was supported in part by a grant from Hoffman LaRoche Canada     

Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen

Aim The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.Methods A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m² per day followed by a 5-FU bolus 400 mg/m² per day and a 22-h 5-FU continuous infusion 600 mg/m² per day for two consecutive days every 2 weeks), and the AUC in mg·h/l·m² was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC 5, by 100% for AUC >5–10, by 50% for AUC >10–15, and by 25% for AUC >15–20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.Results Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5–1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23–50%) in the intention-to-treat population and 47% (95% CI 29–65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).Conclusions This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.     

奥沙利铂联合氟脲嘧啶与甲酰四氢叶酸治疗晚期大肠癌临床观察

目的：观察奥沙利铂联合化疗治疗晚期大肠癌的临床疗效。方法：33例晚期大肠癌患者，用奥沙早铂（Oxaliplatin,L-OHP由法国赛诺菲公司生产，商品名为乐沙定Eloxatin)130mg/m^2，静脉滴注2小时；甲酰四氢叶酸（CF）200mg/m^2，静脉滴注2小时；5－氟脲嘧啶（5－FU）0.5g在CF滴完后静推，然后5－FU3.0g/m^2用一次性便携式静脉输液器持续静脉滴注48小时，每3周1重复1次，治疗2周期后评定疗效，有效病例在4周后确认疗效。结果：33例中CR3例，PR13例，SD13例，PD4例，总有效率（CR＋PR）48．5％。毒副作用主要是Ⅰ-Ⅱ度恶心呕吐，腹泻，感觉神经毒性，粘膜炎，骨髓抑制，静脉炎等。结论：奥沙利铂联合5－FU＋CF治疗晚期大肠癌效果良好，不良反应能耐受，值得临床推广使用。     

Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases

Aim

The aim of this study was to assess chemotherapy associated hepatotoxicity after 3 months' treatment and to correlate patterns of hepatotoxicity with perioperative morbidity.

Methods

Liver specimens of 50 patients with liver metastases from colorectal cancer receiving XELOX or FOLFOX4 for six cycles and 13 specimens of non-chemotherapy patients subjected to liver resection were analyzed. Different patterns of hepatotoxicity were evaluated according to widely accepted pathohistological scores. Furthermore, the histomorphological findings were correlated with perioperative morbidity.

Results

Steatosis grades did not differ among the chemotherapy treated groups and non-chemotherapy patients. Chemotherapy showed an independent effect on fibrosis stage. Age and chemotherapy were independently associated with sinusoidal dilatation. Centrilobular vein fibrosis correlated with administration of chemotherapy. Higher fibrosis stages were associated with increased transfusion requirements.

Conclusion

XELOX and FOLFOX4 do not correlate with the development of steatosis or steatohepatitis. We do not detect a difference in liver injury between the XELOX and FOLFOX4 group. Although 5-fluorouracil based chemotherapy may cause profound changes in liver parenchyma, it can be safely applied. However, age and oxaliplatin predispose for the development of sinusoidal dilatation; therefore caution must be taken in old patients treated with oxaliplatin.     

Treatment of colorectal cancer in the elderly

Colorectal cancer has a high incidence, and approximately 60% of colorectal cancer patients are older than 70, with this incidence likely increasing in the near future. Elderly patients (> 70-75 years of age) are a very heterogeneous group, ranging from the very fit to the very frail. Traditionally, these patients have often been under-treated and recruited less frequently to clinical trials than younger patients, and thus are under-represented in publications about cancer treatment. Recent studies suggest that fit elderly patients can be treated in the same way as their younger counterparts, but the treatment of frail patients with comorbidities is still a matter of controversy. Many factors should be taken into account, including fitness for treatment, the wishes of the patient and family, and quality of life. This review will focus on the existing evidence for surgical, oncologic, and palliative treatment in patients over 70 years old with colorectal cancer. Careful patient assessment is necessary in order to individualize treatment approach, and this should rely on a multidisciplinary process. More well-designed controlled trials are needed in this patient population.