Abstract Background The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free ...survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing. Patients and methods Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3–4) and six NRAS codons (exons 2–4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%). Results Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours ( n = 87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 95% confidence interval 1.36–8.17; P = 0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation ( KRAS exon 2 or other RAS ), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4. Conclusion Patients with RAS -mutant mCRC, as defined by mutations in KRAS and NRAS exons 2–4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.
Clinicians managing colorectal cancer patients need to appreciate that more than 60% of their patients are >70 years of age, and that these proportions may increase further in the future. Many will ...have co-morbidity and frailty issues and in an era of rapidly expanding therapeutic options, this may present formidable challenges. We present the SIOG updated recommendations for managing such patients.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members.
Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for ...this conversion strategy needs further evaluation.
Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012.
Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 95% confidence interval (CI) 27.2–44.2 months arm A: 35.8 (95% CI 28.1–43.6), arm B: 29.0 (95% CI 16.0–41.9) months, HR 1.03 (95% CI 0.66–1.61), P = 0.9. The median PFS was 10.8 (95% CI 9.3–12.2) months arm A: 11.2 (95% CI 7.2–15.3), arm B: 10.5 (95% CI 8.9–12.2) months, HR 1.18 (95% CI 0.79–1.74), P = 0.4. Patients who underwent R0 resection (n = 36) achieved a better median OS 53.9 (95% CI 35.9–71.9) months than those who did not 21.9 (95% CI 17.1–26.7) months, P < 0.001. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8–14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%).
This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for ‘conversion’ treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional ‘line of therapy’ in those patients who are not cured.
NCT00153998, www.clinicaltrials.gov.
Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and ...colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.
Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients >70 years of age. Elderly CRC patients, however, are ...understaged, undertreated and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing the potential for developing guidelines for the treatment of elderly (geriatric) CRC patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. It is hoped that these will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients ...with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy. Of the 1025 patients with induction failure, 875 (median age 55 years) received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine combined with mitoxantrone (HAM; n=150), with all-trans retinoic acid (A; A-HAM) (n=247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n=140), other intensive regimens (n=165), experimental treatment (n=27) and direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (complete remission/complete remission with incomplete hematological recovery (CR/CRi)) was associated with GO-A-HAM treatment (odds ratio (OR), 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10-year difference, 0.75; P<0.0001). Better survival probabilities were seen in an extended Cox regression model with time-dependent covariables in patients responding to salvage therapy (P<0.0001) and having the possibility to perform an allo-HCT (P<0.0001). FLT3 internal tandem duplication, mutated IDH1 and adverse cytogenetics were unfavorable factors for survival.
Background: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of ...metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). Patients and methods: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m2 i.v. on days 1, 15 and 22); FA (200 mg/m2 i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m2 i.v. bolus, then 22-h, 600 mg/m2 infusion) or CAPIRI: irinotecan (250 mg/m2 i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m2 b.i.d. on days 1–15 and 22–36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 × 200 mg b.i.d.). Results: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). Conclusion: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.
To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid FA) can prolong progression-free survival (PFS).
Four ...hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie AIO arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214).
The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001).
The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.
We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 ...mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1
/ASXL1
(OS, P=0.004), RUNX1
/SRSF2
(OS, P=0.007) and RUNX1
/PHF6
(OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1
/IDH2
(OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.
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 ≥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 ≥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.
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