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Randomised study of tegafur–uracil plus leucovorin versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer — TLC study

Open AccessPublished:June 11, 2015DOI:https://doi.org/10.1016/j.jgo.2015.05.004

      Abstract

      Background

      Prospective data on chemotherapy for (frail) elderly patients with advanced colorectal cancer (aCRC) are scant. UFT/leucovorin might be as effective as and less toxic than capecitabine. We firstly randomized both agents in patients >65 years with aCRC not amenable to receive combination chemotherapy.

      Patients and Methods

      Patients were randomised between first-line oral UFT/leucovorin and capecitabine in a Dutch multicentre trial. Primarily, efficacy and toxicity were determined. Secondary, quality of life (QoL) and abbreviated common geriatric assessment (aCGA) were analysed.

      Results

      Sixty-seven patients were randomised with a median age of 77 years and 96% being frail. After interim analysis it was decided to stop recruitment because of low accrual. At a median follow up of 34 months, the median progression-free survival (PFS) and overall survival (OS) were similar for both therapies, being 21 weeks (p = 0.17) and 12 months (p = 0.83), respectively. The overall response rates were 24% and 21%, respectively. Two patients died of possible treatment related complications in the UFT/leucovorin arm and 3 patients in the capecitabine arm. For UFT/leucovorin significantly less grade 3 or 4 hand/foot syndrome (0 vs 5) was observed. Overall, PFS was related to Charlson-comorbidity index (p = 0.049), LDH (p = 0.0011) and albumin (p = 0.009). OS was related to LDH (p = 0.0003), albumin (p = 0.0001), QoLC30/CR38 (p = 0.041), QoL visual analogue scale (VAS; p = 0.016), and GFI (p = 0.028).

      Conclusion

      UFT/leucovorin and capecitabine had similar efficacy and different toxicity profiles in frail elderly patients with aCRC. Baseline serum levels of albumin and LDH, Charlson-comorbidity index, GFI and QoL were prognostic for clinical outcome.

      Keywords

      1. Introduction

      About 70% of patients with colon cancer are >65 years of age and the number of elderly patients is increasing, both due to an increase in life expectancy and the increasing population.
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      • Nordlinger B.
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      • Cervantes A.
      • On behalf of the ESMO Guidelines Working Group
      Primary colon cancer: ESMO clinical practice guidelines for diagnosis, adjuvant treatment and follow-up.
      Despite this growing colorectal cancer burden in elderly patients the majority of studies exploring the optimal strategy in patients with advanced colorectal cancer (aCRC) is based on studies in patients that are considerably younger. Elderly patients more often have co-morbidity and for them combination chemotherapy can be associated with greater toxicity and less overall benefit.
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      Greater risks of chemotherapy toxicity in elderly patients with cancer.
      Currently, the most common first line chemotherapy for treatment of patients with aCRC unsuitable to receive combination chemotherapy or mono-chemotherapy with bevacizumab, is monotherapy with a fluoropyrimidine. Both 5-fluorouracil prodrugs UFT, tegafur plus uracil that inhibits dihydropyrimidine dehydrogenase the rate-limiting enzyme in 5-fluorouracil catabolism, and capecitabine have already shown good tolerability and efficacy in the elderly.
      • Tsutsumi S.
      • Yamaguchi S.
      • Tsuboi K.
      • et al.
      Oral regimen consisting of UFT/UZEL for elderly patients with colorectal cancer.
      • Feliu J.
      • Salud A.
      • Escudero P.
      • et al.
      XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer.
      However, these agents have never been compared in a randomised study. We hypothesised that the different patterns of toxicity may result in a preferable drug for this population. In addition, this study would add to the limited prospective data on elderly patients with aCRC s treated with first line systemic palliative chemotherapy. We therefore initiated this randomised trial comparing UFT and capecitabine in elderly patients with aCRC not suitable for or not willing to receive combination chemotherapy. In order to better monitor the study population we measured, in addition to efficacy and toxicity of the two oral treatments, serum levels of albumin and LDH, quality of life (QoL) and an abbreviated comprehensive geriatric assessment (aCGA).

      1.1 Study Population

      Patients were eligible for inclusion if they were at least 65 years of age, had histologically proven aCRC, measurable disease, not amenable to treatment with curative intent and not amenable or willing to receive combination chemotherapy or mono-chemotherapy with bevacizumab. Patients also had to have a WHO performance score 0–2, a life expectancy of >3 months, and adequate bone marrow, liver and renal function. Frailty was defined as having two or more comorbidities according to the Charlson co-morbidity index and/or a Gronigen frailty indicator (GFI) score >4. Patients were excluded from the study if they had received prior chemotherapy for aCRC (prior adjuvant chemotherapy was allowed provided that the last administration was given > 6 months prior to randomisation), known or suspected central nervous system metastasis, another malignancy in the previous 5 years (with exception of a history of previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix), chronic diarrhoea or inflammatory bowel disease, known as dihydropyrimidine dehydrogenase (DPD) deficiency, clinically relevant coronary artery disease, a high risk of uncontrolled arrhythmia, or history of myocardial infarction in the last 12 months or a medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent. The study was approved by the Ethics Committees of the Leiden University Medical Center and all local participating institutions. Written informed consent was obtained from all patients.

      1.2 Treatment and Evaluation

      After randomisation patients received UFT/leucovorin (UFT 150 mg/m2 orally, b.i.d, plus leucovorin 30 mg, b.i.d., days 1–28, Q5 weeks) or capecitabine (1250 mg/m2, b.i.d, days 1–14, Q3 weeks) until disease progression or unacceptable toxicity in the TLC study (NTR1268, Dutch trial register, www.trialregister.nl).
      Toxicity was graded according to the common toxicity criteria for adverse events (CTCAE), version 3.0. Patients were assessed clinically at least every 5 weeks and response evaluation was carried out every 9 weeks during therapy and at the end of study treatment, using RECIST criteria version 1.0. Questionnaires on QoL, using the EORTC QoL Questionnaire C-30, CR38 and visual analogue scale (VAS), and an aCGA were completed at study entry. The surveys were planned to be administered prior to randomization, and thereafter every 9 weeks with a final survey at the end of treatment. The aCGA examined the co-morbidity (Charlson co-morbidity index, cut-off score >2),
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      • Pompei P.
      • Ales K.L.
      • Mackenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      instrumental activities of daily life (IADL; cut-offs for partial dependence 14–27, full functional dependence <13),
      • Lawton M.P.
      Scales to measure competence in everyday activities.
      geriatric depression scale (GDS; cut-off for severe depressive symptoms >10, moderate depressive symptoms 5–9),
      • Sheikh J.I.
      • Yesavage J.A.
      • Brooks III, J.O.
      • Friedman L.
      • Gratzinger P.
      • Hill R.D.
      • et al.
      Proposed factor structure of the geriatric depression scale.
      and Groningen Frailty Index (GFI; cut-off of 4 or more for frailty).
      • Slaets J.P.
      Vulnerability in the elderly: frailty.
      Subgroup analyses of PFS and OS were performed for baseline patients characteristics (WHO performance score and age), baseline serum levels of LDH <400 vs >400 and albumin <35 vs >35, QOL and aCGA.

      1.3 Statistical Methods

      The primary end point of the study was progression free survival (PFS), defined as the duration from the time of randomisation until first observation of radiologically confirmed progressive disease or death due to any cause, whichever occurred first. Secondary endpoints included overall survival (OS) defined as the duration from the time of randomisation until death from any cause, objective response rate, toxicity and the evaluation of QoL and aCGA.
      Assuming that the treatments have a similar hazard of progression, it was considered that only differences in the median PFS of >6 weeks (HR = 1.4 UFT/capecitabine) were medically relevant. With 277 events, the upper limit of the confidence interval of the hazard ratio would not exceed 1.4 with 80% power and a sample size of 300 patients.
      Randomisation was stratified by WHO performance status (0–1 vs. 2), age (65–69, 70–79, and >80 years) and prior adjuvant therapy (with fluoropyrimidine vs. without a fluoropyrimidine vs. any prior adjuvant therapy). If the difference in PFS was not medically relevant, the choice of treatment would be based on other considerations: better QoL or less toxicity.
      All end points were analysed according to the intention-to-treat principle, except toxicity which included only patients who received at least one therapy dose. The analyses of PFS and OS by treatment were based on the stratified log-rank test. The Kaplan–Meier method was used to estimate PFS and OS curves and hazard ratios were calculated using Cox proportional hazards models. Two sided p-values are presented.

      2. Results

      2.1 Conduct of the Trial

      Between January 8, 2008 and July 30, 2012, 15 participating Dutch hospitals enrolled a total of 67 patients. An interim analysis on grade 3/4 adverse events was done in December 2011 after inclusion of 46 patients. This test, with 1-sided significance level 0.05 and 90% power for the hypothesis of 40% grade 3/4 adverse events in the capecitabine and 20% in the UFT arm, showed that the futility boundary was not crossed. The study was closed prematurely in July 2012 due to slow accrual, partly because of the introduction of bevacizumab for treatment of first line aCRC. This limited the sample size to 67. The cut-off date for analysis was January 29, 2014, resulting in a median follow up of 34 months. All patients were eligible for efficacy analysis and 66 for toxicity analysis.

      2.2 Patient Characteristics

      Fig. 1 depicts the CONSORT diagram of the study. Patient characteristics are shown in Table 1. The median age was 77 years. Most patients (94%) were >70 years. The median Charlson co-morbidity index was 1 with a range from 0–10. The majority of patients (96%) were frail, defined as having two or more comorbidities, with 22% and 33% of the patients in the UFT and capecitabine arm, respectively and/or a GFI 4–9 score in 94% of patients.
      Table 1Patient characteristics.
      PatientsUFT/leucovorinCapecitabineTotal
      343367
      Age
       Median (range)77 (66–88)76 (66–88)77 (66–88)
       65–692 (6%)2 (6%)4 (6%)
       70–7919 (56%)19 (58%)38 (57%)
       80–8813 (38%)12 (36%)25 (37%)
      Gender
       Male19 (56%)17 (52%)36 (54%)
       Female15 (44%)16 (48%)31 (46%)
      WHO performance status
       010 (30%)6 (20%)16 (25%)
       120 (61%)19 (63%)39 (62%)
       23 (9%)5 (17%)8 (13%)
       NA134
      Charlson co-morbidity index
       Median (range)1 (0–10)1 (0–7)1 (0–10)
      Frailty (Charlson and/or GFI)
       CCI > 2 or GFI > 424 (92%)27 (100%)51 (96%)
       CCI 0–1 and GFI < 32 (8%)0 (0%)2 (4%)
       NA8614
      Disease stage
       IIIA0 (0%)0 (0%)0 (0%)
       IIIB1 (3%)2 (7%)3 (5%)
       IIIC0 (0%)1 (3%)1 (2%)
       IV30 (97%)27 (90%)57 (93%)
       NA336
      Site of primary tumour
       Colon19 (56%)19 (59%)37 (57%)
       Rectum13 (39%)12 (38%)25 (38%)
       Both1 (3%)0 (0%)1 (2%)
      Prior adjuvant therapy
       With a fluoropyrimidine3 (9%)3 (9%)6 (9%)
       Without a fluoropyrimidine1 (3%)0 (0%)1 (1%)
       No prior adjuvant therapy30 (88%)30 (91%)60 (90%)
      CCI = Charlson comorbidity index; GFI = Groningen frailty indicator; NA = not available.

      2.3 Survival and Response Rate

      Sixty-five of the 67 patients had a PFS event, 33 in the UFT/leucovorin group and 32 in the capecitabine group. The median PFS was 20 weeks (95% confidence interval (CI) 19.5–27.6) in the UFT/leucovorin group and 23 weeks (95% CI 13.4–40.4) in the capecitabine group, hazard ratio (HR) 0.66 (95% CI 0.37–1.19, p = 0.17, Fig. 2a ).
      Figure thumbnail gr2
      Fig. 2a: Progression free survival UFT/lV vs capecitabine (stratified logrank test p = 0.17). b: Progression free survival by Charlson index (logrank test p = 0.049).
      No significant difference in overall survival (OS) was observed between the chemotherapy regimens (Fig. 3). Median OS was 12 months (95% CI 8–16 months) for UFT/leucovorin and 13 months (95% CI 5–17 months) for capecitabine (HR 0.94;95% CI 0.52–1.70; p = 0.83).
      Figure thumbnail gr3
      Fig. 3a: Overall survival UFT/LV vs capecitabine (stratified logrank test p = 0.83). b: Overall survival by Qol (logrank test p = 0.041). c: Overall survival by VAS (logrank test p = 0.016). d: Overall survival by GFI (logrank test p = 0.028).
      The best overall response rate percentages were 24% (all partial responses) for UFT/leucovorin and for capecitabine 21% (2 complete responses and 5 partial responses, Table 2).
      Table 2The best overall response and reasons for non-evaluability.
      Randomized treatment
      UFTCapecitabineTotal
      Patients343367
      Best overall response
       Complete response0 (0%)2 (6%)2 (3%)
       Partial response8 (24%)5 (15%)13 (19%)
       Stable disease11 (32%)11 (33%)22 (33%)
       Progressive disease6 (18%)7 (21%)13 (19%)
       Not evaluable9 (26%)8 (24%)17 (25%)
      Reasons for non-evaluability
       Not finished enough cycles to evaluate response (<3 cycles)9614
       Never started therapy011
       Clinical PD (not measured)011

      2.4 Baseline Quality of Life and Comprehensive Geriatric Assessment

      Baseline QLQ-C30 and -CR38 questionnaires were available from 60/67 and 52/67 patients respectively. Baseline co-morbidity was known from 55/67 patients. Baseline IADL, GDS, GFI and VAS was known from 54, 54, 51 and 39 out of 67 patients, respectively. All missing questionnaires were well-balanced between the arms.
      Subgroup analyses for PFS were performed for all patients combined as well as compared between the 2 chemotherapy regimens. For all patients combined, PFS was significantly higher for those without co-morbidity as compared to those with a Charlson comorbidity index >2 (Fig. 2b; log rank test p = 0.049). PFS was almost statistically significantly different for Charlson comorbidity index with optional age extension (p = 0.07) and for age (p = 0.10), and not different for QoL (p = 0.57), IADL (p = 0.45), GDS (p = 0.14), VAS (p = 0.64) and GFI (p = 0.82).PFS was significantly related to serum LDH (p=0.0011) and albumin (p=0.009) (Fig.4).
      Figure thumbnail gr4
      Fig. 4a: Progression free survival by albumin (logrank test p = 0.009). b: Progression free survival by LDH (logrank test p = 0.0011). c: Overall survival by albumin (logrank test p = 0.0001). d: Overall survival by LDH (logrank test p = 0.0003).
      OS was significantly related to baseline WHO performance score (p = 0.042), serum LDH (p = 0.0011) and albumin (p = 0.009), QoL (p = 0.041), VAS (p = 0.016) and GFI (p = 0.028).
      The subgroup analyses for all these variables in terms of PFS and OS showed no difference between the 2 chemotherapy regimens.

      2.5 Toxicity

      The safety population consisted of 66 patients in the randomised population who received any dose of study drug (one patient in the capecitabine arm, who did not start therapy, was excluded). Adverse events of CTC grade 3 or higher were considered. During treatment, there were 56 > grade 3 adverse events, 28 events in both arms (Table 3). Two patients died of possibly treatment related complications in the UFT/leucovorin arm (pulmonary embolus and unknown reason) and 3 in the capecitabine arm (1 dyspnoea and 2 ischemic CVA). Only 2 patients developed grade >3 hematologic toxicity. Five patients, all in the UFT/leucovorin group received erythropoietin and only one patient in the capecitabine arm had a grade 3 anaemia. For UFT/leucovorin there seemed to be more grade 3/4 diarrhoea (9 vs 4 patients, although not statistically significant p = 0.22), but there was significantly less grade 3/4 hand/foot syndrome (0 vs 5 patients, p = 0.023).
      Table 3Grade 3–5 adverse events (CTCAE v 3.0).
      Randomised treatment
      UFTCapecitabine
      Grade 3Grade 4Grade 5Grade 3Grade 4Grade 5Total
      Anorexia415
      Acute coronary syndrome11
      Constipation11
      CVA, ischaemic22
      Diarrhoea72413
      Dyspnoea11
      Haematology112
      Hand–foot-skin reaction55
      Hyperbilirubinemia213
      Hypertension22
      Infection112
      Nausea112
      Pain3137
      Pulmonary embolus11
      Skin/rash11
      Stomatitis/mucositis112
      Thrombosis/embolism1113
      Unknown11
      Vomiting22
      Any adverse event2332232356
      Adverse events >grade 3 were not related to baseline co-morbidity, quality of life or one of the other aCGAs.

      2.6 Treatment Duration

      A median of 4 cycles of chemotherapy were administered for both UFT/leucovorin and capecitabine with a range of 1–8 and 0–21, respectively. A dose reduction was applied for UFT/leucovorin in 15/34 (44%) patients after a median of 43 days and for capecitabine in 15/33 (47%) after a median of 44 days. Reasons for permanent treatment cessation for UFT/leucovorin and capecitabine were toxicity (15 vs 33%), progressive disease (65 vs 39%), patient refusal (both 9%), death (both 6%) and other reasons (6%: investigator decision that included the patients condition and radiofrequency ablation, vs 12%: not eligible according to exclusion criteria, investigator decision because of the patients condition, CVA, liver surgery, delayed restart of chemotherapy).

      3. Discussion

      In this multicenter randomised phase III study in elderly patients with aCRC, for the first time, two oral 5-fluorouracil analogues were compared; tegafur–uracil/leucovorin and capecitabine. Efficacy defined by response rate, PFS and OS was similar for both agents. However, as this study was closed prematurely owing to poor accrual it may have failed to meet its primary end point of showing a difference in PFS between the two arms. Therefore, data in these elderly patients on toxicity, QoL, and geriatric indexes and on toxicities between the regimens was of more importance.
      Sequential treatment, starting with first-line fluoropyrimidine monotherapy, is a valid alternative, for advanced colorectal cancer, to combination chemotherapy in the majority of patients with metastatic colorectal cancer.
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      Although the majority of patients in the trial was frail elderly, efficacy results with a median OS of 12 months are comparable to earlier trials with less frail patients. In Phase III trials that compared both agents separately with 5-fluorouracil/leucovorin, an OS of 12 months for UFT/leucovorin
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      Simplified prognostic model in patients with oxaliplatin-based or irinotecan-based first-line chemotherapy for metastatic colorectal cancer: a GERCOR study.
      Also, QOL, co-morbidity and GFI have been previously associated with clinical outcome in elderly patients.
      • Extermann M.
      • Hurria H.
      Comprehensive geriatric assessment for older patients with cancer.
      • Aaldriks A.A.
      • Maartense E.
      • le Cessie S.
      • Giltay E.J.
      • Verlaan H.A.
      • van der Geest L.G.
      • Kloosterman-Boele W.M.
      • Peters-Dijkshoorn M.T.
      • Blansjaar B.A.
      • van Schaick H.W.
      • Nortier J.W.
      Predictive value of geriatric assessment for patients older than 70 years, treated with chemotherapy.
      To the best of our knowledge, the use of VAS for QoL has not been related to outcome in the elderly before. Importantly baseline LDH, albumin and VAS are relatively easy to obtain. With the growing incidence of cancer in elderly patients, understanding of chemotherapy sensitivity and toxicity with an emphasis on patient selection by a reliable and efficient aCGA is becoming essential.
      Since February 2013 the trade licence for UFT expired in Europe. In Japan, Taiwan, South Korea, Singapore and Malaysia, UFT is still commercially available. The oral fluoropyrimidine, S-1, might become the successor of UFT. S-1 consists of tegafur combined with two biochemical fluorouracil modulators. It has shown good efficacy combined with oxaliplatin, has a similarly favourable toxicity profile to UFT and is currently being tested in phase III trials.
      • Hong Y.S.
      • Park Y.S.
      • Lim H.Y.
      • Lee J.
      • Kim T.W.
      • Kim K.P.
      • Kim S.Y.
      • Baek J.Y.
      • Kim J.H.
      • Lee K.W.
      • Chung I.J.
      • Cho S.H.
      • Lee K.H.
      • Shin S.J.
      • Kang H.J.
      • Shin D.B.
      • Jo S.J.
      • Lee J.W.
      S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial.
      Our trial has some limitations. Firstly the study was closed prematurely due to slow accrual, partly because of the registration of bevacizumab for treatment of first line aCRC, which resulted in the inclusion of mostly frail patients not suitable for or not willing to receive combination chemotherapy or mono-chemotherapy with bevacizumab. Frail patients are less amenable to receive chemotherapy and frail patients often start with chemotherapy at a lower dose. However, now we have data on the usage of chemotherapy in a unique population of frail patients. During treatment, a dose reduction was necessary in almost half of the patients.
      Secondly, the patients in our study underwent an aCGA after the medical oncologist decided that they were eligible to receive chemotherapy, which may have introduced some selection bias. Furthermore, we did not screen parameters like nutritional status and mini-mental state examination (MMSE). However, we could therefore minimise the burden of testing which resulted in good compliance (>80%).
      In conclusion, this is one of the few randomised studies in frail elderly patients with aCRC. It shows that UFT/leucovorin and capecitabine had similar efficacy and dissimilar toxicity profiles in favour of UFT. In this frail population we identified QoL using VAS as a new prognosticator for clinical outcome and were able to confirm that baseline serum levels of LDH and albumin, Charlson co-morbidity index, Qol and GFI were predictors for clinical outcome.

      Disclosures and Conflict of Interest Statements

      This study was financially assisted with funds from Merck KGaA and Janssen-Cilag BV. All remaining authors have declared no conflicts of interest.

      Author Contributions

      Study concept: H Gelderblom, JWR Nortier, JR Kroep.
      Study design: H Gelderblom, JWR Nortier, JR Kroep, AM Stiggelbout, E van Werkhoven.
      Data acquisition: E van Werkhoven, JR Kroep.
      Quality control of data and algorithms: E van Werkhoven, AM Stiggelbout.
      Data analysis and interpretation: JR Kroep, E van Werkhoven, M Polee, CJ van Groeningen, A Beeker, F Erdkamp, N Weijl, A van Bochove, Z Erjavec, E Kapiteijn, AM Stiggelbout, JWR Nortier, H Gelderblom.
      Statistical analysis: E van Werkhoven.
      Manuscript preparation: JR Kroep, E van Werkhoven, H Gelderblom.
      Manuscript editing: JR Kroep.
      Manuscript review: JR Kroep, E van Werkhoven, M Polee, CJ van Groeningen, A Beeker, F Erdkamp, N Weijl, A van Bochove, Z Erjavec, E Kapiteijn, AM Stiggelbout, JWR Nortier, H Gelderblom.

      Funding

      This work was supported by a grant from Merck KGaA, The Netherlands and Janssen-Cilag BV, The Netherlands.

      Acknowledgements

      The authors thank all the patients that participated and the other investigators participating in this study.

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