Five deaths might have been treatment-related one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group. Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting.
Funding: Cancer Research UK. Published by Elsevier Ltd. Search for terms. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : December 5, Last Update Posted : February 10, Study Description. The purpose of this study is to evaluate the change in patient-reported outcomes, physician assessment of a change as well as safety and tolerability in patients with Relapsing Forms of Multiple Sclerosis on previous Disease Modifying Therapy DMT who are randomized to one of two treatment arms: fingolimod vs.
MedlinePlus related topics: Multiple Sclerosis. Drug Information available for: Fingolimod Fingolimod hydrochloride. FDA Resources. Arms and Interventions. Outcome Measures. The Fatigue Severity Scale FSS is a 9-item assessment scale measuring fatigue and its effects, using a scale from 1 to 7, with higher scores indicating greater fatigue, or greater negative effects of fatigue on daily living. The effectiveness scale was scored as follows: 1 extremely dissatisfied to 7 extremely satisfied.
The Side Effects subscale was scored as follows: question 4 scored as 0 no or 1 yes ; question 5 scored as 1 extremely bothersome to 5 not at all bothersome ; and questions 6 - 8 scored as 1 a great deal to 5 not at all.
The convenience subscale was scored as follows: questions 9 and 10 scored as 1 extremely difficult to 7 extremely easy , and question 11 scored as 1 extremely inconvenient to 7 extremely convenient. The SFv2 is a validated health-related quality of life instrument used in numerous disease states, including MS. The CGI-I is a rating scale allowing a physician-reported global evaluation of the subject's improvement over time.
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First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes EPOC study in relapsing multiple sclerosis.
Treatment defaulted to standard of care, which, for most patients, was continuation of chemotherapy alone. Data collection to inform outcomes was continued. The primary outcome was progression-free survival, which was defined as the time from randomisation to disease progression or death from any cause, whichever occurred first, and has been previously reported.
The objective of this present study was to assess the secondary endpoint of overall survival, defined as the time from randomisation to death from any cause. Patients still alive were censored at the time of last follow-up. As such, the assumption was made that any patient not recorded as having died could be assumed alive and censored 2 months before the NHS Digital date of assessment of patient status ie, this excluded the possibility of missing a death event as the death had not yet reached the NHS Digital database.
For the evaluation of progression-free survival, patients lost to follow-up without progression were censored at the date of the last assessment, irrespective of whether or not the date of death was received subsequently via NHS Digital.
Quality-of-life and cost-effectiveness analyses were not done because the trial was negative. Other prespecified exploratory outcomes were post-progression survival in the primary analysis population who progressed and progression-free survival and overall survival in: patients treated with oxaliplatin, fluorouracil, and folinic acid; patients who responded to preoperative chemotherapy; patients with left-sided cancers; and patients with right-sided cancers.
All analyses presented were prespecified in the statistical analysis plan that was updated for this mature analysis appendix pp — The accrual target of the study was revised on Jan 16, , at the suggestion of the trial steering committee after a reconsideration of the potential effect of KRAS wild-type restriction. There was no correction of the p value to adjust for the previous analysis. An a-priori statistical analysis plan was devised for all analyses of these long-term data.
Survival was described using Kaplan-Meier curves and compared using Cox proportional hazards models. Safety analyses included all randomly assigned patients and involved calculating frequencies and percentages.
There was no adjustment for multiple comparisons. The primary analysis used an unadjusted Cox proportional hazards model, but a sensitivity analysis was also done, adjusting the model for the minimisation factors. For all Cox proportional hazards models fitted, the assumption of proportional hazards was checked by visually inspecting the complementary log-log event times versus log time plot.
STATA version Data were reviewed by the Data Monitoring and Ethics Committee. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
TM, AW, and LS had full access to all the data in the study and all authors had final responsibility for the decision to submit for publication. One patient was incorrectly assigned by mistake ie, the patient was eligible but the centre was asked to proceed with the opposite treatment to the one they had been assigned to , and was excluded from all analyses. An additional 14 patients six in the chemotherapy alone group and eight in the chemotherapy plus cetuximab group , who were randomly assigned before the amendment necessitating KRAS status testing and were retrospectively shown to have a KRAS mutation or indeterminate KRAS status, were also excluded from all analyses, except safety analyses.
As such, the primary analysis population consisted of patients, of whom patients were randomly assigned to received chemotherapy alone and to receive chemotherapy plus cetuximab figure 1.
One patient assigned to the chemotherapy plus cetuximab group was lost to follow-up. Table 1 shows the baseline characteristics, similar to those published previously. The patients who had previous oxaliplatin adjuvant therapy or another contraindication to oxaliplatin were treated using regimen 3.
Data on relative dose intensity are in the appendix pp 19— For the progression-free survival updated analysis there were events 89 in the chemotherapy alone group and 91 in the chemotherapy plus cetuximab group; since the preliminary analysis in , 57 additional events had occurred [33 in the chemotherapy alone group and 24 in the chemotherapy plus cetuximab group]. Progression-free survival A and overall survival B in the primary analysis population. The response to preoperative chemotherapy is shown in the appendix p Surgical information is presented in table 2.
The numbers in this table represent all surgeries carried out. Patients who had their resection staged are counted twice as this information was recorded for each surgery.
The progression-free survival and overall survival in patients in the primary analysis population treated with the chemotherapy backbone of oxaliplatin, 5-fluorouracil, and folinic acid and in the subpopulations of patients who responded to preoperative chemotherapy, who had left-sided cancers, and who had right-sided cancers were explored in prespecified analyses and are shown in the appendix pp 6—9, 12— The results from the interaction subgroup analysis of overall survival and progression-free survival are in figure 3 and the appendix pp 10, All mutations were mutually exclusive.
Treatment-related adverse events are in table 3. There were 26 drug-related serious adverse events in the chemotherapy alone group and 32 in the chemotherapy plus cetuximab group appendix pp 30, 31 There were five deaths potentially related to treatment appendix p Three of these related to systemic treatment, one in the chemotherapy alone group heart failure and two in the chemotherapy plus cetuximab group one pulmonary embolism and interstitial lung disease and one pulmonary embolism.
One patient died of bronchopneumonia within 30 days of surgery in the chemotherapy plus cetuximab group. Another patient died of cardiac arrest within 90 days of surgery in the same treatment group and, although outside the protocol definition, this death might have been related to surgery.
Protocol violations are recorded in the appendix pp 32, The interim analysis of the primary endpoint of the New EPOC study showed a significantly shorter progression-free survival when cetuximab was added to perioperative chemotherapy, for patients with resectable colorectal liver metastasis.
This mature analysis found that the detriment in progression-free survival is no longer significant, although median overall survival was 26 months shorter for patients receiving cetuximab and chemotherapy than for those receiving chemotherapy alone.
This finding suggests that the premature closure of the trial, its primary limitation but mandated by the trial steering committee, did not influence the outcome. If the study were to be repeated, translational endpoints would be prioritised. However, such a choice was neither standard nor technically feasible in , when the study started. The baseline characteristics of the chemotherapy plus cetuximab group are prognostically less favourable, with more patients having synchronous disease and a metastasis larger than 3 cm.
However, these differences are small and not significant. Furthermore, review of the predefined subgroup analyses reveals the detriment with cetuximab in this present study occurred in patients with favourable characteristics not poorly differentiated, not N2 disease, fewer than four metastases. The subset with unfavourable prognostic features poorly differentiated histology, N2 disease, or four or more metastases did not benefit from addition of cetuximab to chemotherapy, but were not disadvantaged.
As such, there is no evidence to suggest that any difference in the baseline variables contributed to the poor outcome of the cetuximab group. The quality of surgery following systemic therapy might have affected study outcome. At the time of the first publication it was not possible to present complete surgical data since not all patients had, at that time, undergone protocol-defined surgery.
These data are now complete. More patients in the chemotherapy plus cetuximab group than in the chemotherapy alone group did not undergo an operation, in most cases because of progressive disease. Of the patients who underwent an operation, some were treated with ablation with or without surgery. This choice was not permitted in the protocol, but patient management was always at the discretion of the clinician.
Additional protocol violations included the two patients in the chemotherapy alone group who were not operated on during the period allowed by the protocol, because of a complete radiological response, and the two patients in the chemotherapy plus cetuximab group who were operated on, but not resected, because of a complete response.
Although it is natural to focus on the unexpected outcome in the experimental group of the trial, the survival achieved in the chemotherapy alone group should not be overlooked. Indeed, the 5-year survival in this group is comparable to the best of any case series, 1 despite the inclusion of borderline resectable patients. Furthermore, there was only one day mortality in the patients that underwent surgery, attesting to the quality of care in high-volume liver surgery centres in the UK.
Data to support a biological explanation for this unexpected trial outcome are accumulating. High expression of the microRNA miR—3p in primary colorectal cancer of patients with metastatic disease treated with cetuximab or panitumumab has been shown to be associated with resistance to EGFR and disease progression.
This detrimental effect was not observed in patients with low miR—3p expression levels. In , survival benefit from the use of panitumumab in advanced colorectal cancer was observed in patients with high AREG or EREG expression, or both, but not in those with low expression. Mismatch repair status was not routinely measured during the period of study recruitment and cannot be reliably reported. This will be assessed in the translational analysis.
Although studies of anti-EGFR therapies in advanced disease have mostly been positive, those in the adjuvant setting have not, 22 , 23 with a trend towards detrimental outcomes in older patients. Furthermore, and as discussed above, the survival of patients with poorer prognostic features did not seem to be affected by the addition of cetuximab.
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