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![an absolute survival benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-
0.97; p=0.003).
The benefit was significantly higher with hyperfractionated radiotherapy (8%
at 5 years) than with accelerated radiotherapy
There was a benefit on locoregional control in favour of altered fractionation
versus conventional radiotherapy (6.4% at 5 years; p<0.0001),
The benefit was significantly higher in the youngest patients
(hazard ratio 0.78 [0.65-0.94] for under 50 year olds,
0.95 [0.83-1.09] for 51-60 year olds,
0.92 [0.81-1.06] for 61-70 year olds,
and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007).](https://image.slidesharecdn.com/journalclubmarchanalysis-250406143242-881d3244/75/Journal-Club-MARCH-analysis-adjuvant-radiotherapy-pptx-17-2048.jpg)
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Journal Club MARCH analysis (adjuvant radiotherapy).pptx
- 1. Journal Club MARCH analysis DrMaroti FHNO Fellow
- 2. What is Meta-analysis? Meta-analysisis a statistical method that combines results from multiple studies on the same topic to provide a more comprehensive and precise estimate of the association between an exposure and an outcome, essentially creating a "pooled analysis" by combining data from different studies, allowing for stronger conclusions
- 3. Systematic reviews vsmeta-analysis: what’s the difference?
- 6. What is forestplot?
- 10.
- 12. Introduction Altered fractionation radiotherapyis believed to be effective through two mechanisms that together improve the therapeutic ratio: 1. the delivery of small fractions twice per day reduces the frequency of late toxicity, allowing for higher total doses of radiation to be delivered than can be achieved with conventional dosing; 2. and the shortening of the overall treatment time limits tumour repopulation
- 13.
- 14. Summery ➔ Randomised trialscomparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy ➔ 15 trials with 6515 patients ➔ median follow-up was 6 years altered fractionation radiotherapy is associated with ➔ improved overall survival and progression-free survival
- 15.
- 16.
- 17. an absolute survivalbenefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86- 0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007).
- 18. Aim provide an update,aiming to confirm and explain the superiority of hyperfractionation over the other altered fractionation regimens, to assess the benefit of altered fractionation within the context of concomitant chemotherapy or postoperative trials, and to provide a direct comparison of altered fractionation with conventional fractionation concomitant chemoradiotherapy.
- 19. Altered fractionation radiotherapyis believed to be effective through two mechanisms that together improve the therapeutic ratio: ❖ the delivery of small fractions twice per day reduces the frequency of late toxicity, allowing for higher total doses of radiation to be delivered than can be achieved with conventional dosing; ❖ the shortening of the overall treatment time limits tumour repopulation
- 20. Methods PubMed, Web of Science, theCochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings for randomised trials published or presented between Jan 1, 2009, and July 15, 2015
- 21. comparison 1- compareprimary or postoperative conventional fractionation radiotherapy with altered fractionation radiotherapy (with or without the same concomitant chemotherapy in both groups) comparison 2- conventional fractionation radiotherapy plus concomitant chemoradiotherapy versus altered fractionation radiotherapy without concomitant chemotherapy
- 22. started randomisation onor after Jan 1, 1970, completed accrual before Dec 31, 2010, and included patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Eligible trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated.
- 23. Data extraction andchecking 1. patient and tumour characteristics, 2. dates of randomisation, 3. failures and death, 4. treatment group allocated, 5. details about treatments received, and 6. acute and late toxicities.
- 24. Outcomes primary endpoint -overall survival, Secondary endpoints - progression-free survival; local, regional, and locoregional failures; distant failure; cancer and non-cancer mortality; and non-hematologic toxicities.
- 25. Statistical analysis median follow-upwas calculated with the reverse Kaplan-Meier method individual and overall pooled hazard ratios (HRs) with 95% CIs through a fixed- effects model using the log-rank expected number of events and variance and OR calculated with similar model Stratified survival curves were estimated for control and experimental groups using annual death rates and hazard ratios, and absolute differences at five and ten years with their 95% CI Cancer mortality was obtained indirectly by subtracting the log-rank statistic for non-cancer mortality from the log-rank statistic for mortality from all causes
- 26. Stats… Overall survival after5 years was obtained indirectly by subtracting the log-rank statistic for overall survival within 5 years from the log-rank statistic for overall survival on the whole period of time. Computed residual heterogeneity within trial subgroups by subtracting the χ2 statistic of the heterogeneity test between groups from the χ2 statistic of the overall heterogeneity test. Analyses were done using SAS, version 9.3.
- 27.
- 28. Results 26 new trialspublished between 1995 and 2016 that were not included in the original MARCH analysis. 9 TRIALS EXCLUDED Overall, 34 trials (15 1st MARCH +17 new trials + 2 unpublished) representing 11 969 patients were included in the meta-analysis.
- 29. 33 trials and11 423 patients (36 comparisons, 11 981 patients) were included in comparison 1 (the analysis of fractionation schedules) The analysis of altered fractionation radiotherapy versus conventional fractionation chemoradiotherapy (comparison 2) included five trials
- 33. overall survival wassignificant (p=0·051), the survival benefit being restricted to the hyperfractionated regimen (HR 0·83, 95% CI 0·74–0·92), with absolute differences at 5 years of 8·1% (95% CI 3·4 to 12·8) and at 10 years of 3·9%.
- 34. The moderately acceleratedand very accelerated radiotherapy regimens did not have a significant effect on overall survival compared with conventional radiotherapy
- 36. progression-free survival- conventionalradiotherapy, altered fractionation radiotherapy had a significant Interaction between altered fractionation regimens and the effect on progression-free survival was not significant (p=0·17). Heterogeneity between trials was significant (p=0·045, I2=30%).
- 39. No significant differenceswere reported between conventional radiotherapy and altered fractionation radiotherapy in terms of non-cancer mortality
- 40. Altered fractionation radiotherapywas associated with significantly reduced cancer mortality, local failure, and regional failure
- 41. Moderately accelerated radiotherapywas only associated with a reduction in local failures and very accelerated radiotherapy had no effect on any of these endpoints
- 43. The effect ofaltered fractionation radiotherapy on regional control according to nodal status was studied as an unplanned post-hoc analysis. In the 5592 node-positive patients, we found a significant improvement in regional control with altered fractionation radiotherapy compared with conventional fractionation radiotherapy (HR 0·88, 95% CI 0·79–0·98; p=0·017
- 44. Toxicity The toxicity analysisshowed a significantly increased prevalence of acute mucositis (OR 2·02, 95% CI 1·81–2·26) and need for a feeding tube during treatment (1·75, 1·49–2·05) for patients treated with altered fractionation radiotherapy Acute dermatitis was significantly increased in patients treated with altered fractionation radiotherapy None of the late toxicities with sufficient available data showed an increased prevalence with the use of altered fractionation
- 45. Five trials and986 patients comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy vs altered fractionation radiotherapy alone)- Altered fractionation radiotherapy was associated with a significant decrease in overall survival compared with concomitant chemo radiotherapy (HR 1·22, 95% CI 1·05–1·42; p=0·0098
- 46.
- 47. Discussion ★ altered fractionationradiotherapy was associated with a small but significant improvement in overall survival when compared with standard fractionation radiotherapy (3·1% at 5 years). ★ absolute difference at 5 years was 8·1% for the hyperfractionation group. ★ clear benefit on local control, a smaller benefit on regional (nodal) control and cancer mortality, and no benefit on distant metastases and non- cancer-related mortality. ★ Altered fractionation radiotherapy was associated with increased acute mucositis and need for feeding tube placement but we found no significant difference in late toxicity
- 48. Hyperfractionation was associatedwith a benefit both in local and regional control whereas accelerated regimens only provided an improvement in local control. In node-positive patients, the interaction between altered fractionated regimens and regional control was not significant, but the effect of altered fractionated radiotherapy was significant only for hyperfractionated radiotherapy.
- 49. superiority of concomitantchemoradiotherapy regarding overall survival, progression-free survival, and locoregional control.
- 50. strengths of thismeta-analysis ❏ Size ❏ use of individual patient data, which allowed detailed checking of each trial ❏ Unpublished trials were also included ❏ follow-up of longer than 10 years ❏ large number of patients allowed secondary endpoints to be assessed and subgroup and subset analyses to be done with adequate power
- 51. limitations all of thetrials included used outdated radiotherapy techniques (two- dimensional or three-dimensional radiotherapy), which is a concern because intensity-modulated radiotherapy is the present standard of care (However, the dose-intensity– efficacy association shown in this meta-analysis certainly remains valid) trials also come before the human papillomavirus (HPV) era and often did not record smoking status, with data for these variables available in very few trials in the meta-analysis. trials’ accrual period ranged from 1979 to 2010 and this long time span might add heterogeneity to the meta-analysis quality of data collected for the toxicity analysis
- 52. only five trialscompared altered fractionation radiotherapy with standard radiotherapy plus chemotherapy in both groups, and three trials have a lower dose of chemotherapy in the group with altered fractionation radiotherapy than in the standard radiotherapy group number of endpoints analysed raises the question of multiplicity of testing and the inflation of type I error.
- 53. Ongoing research effortsusing the MARCH database A. extensive analysis of trials that provided information about the pathology findings for patients who have undergone primary surgery followed by postoperative radiotherapy. B. cost-effectiveness analyses comparing concomitant chemoradiotherapy and hyperfractionation radiotherapy without concomitant chemotherap C. health services research to address patients’ and physicians’ difficulties in the implementation of hyperfractionation radiotherapy, and improved documentation of long-term toxicity and patient reported outcomes.
- 54. Comparison MARCH 1 ➔ Publishedin 2006 ➔ 15 Trials ➔ Comparing conventional with hyperfractionated or accelerated RT MARCH 2 ➔ Published in 2017 ➔ 34 Trials ➔ Confirming superiority of Altered fractionation and compared CRT (with conventional) v/s AFRT ➔ Longer median follow up time 7·9 years overall and 10·4 years for the 15 trials previously included in the MARCH meta- analysis. ➔ Data on acute and late toxicity were collected.
- 55. Conclusion efficacy of alteredfractionation radiotherapy over conventional fractionation radiotherapy and the superiority of hyperfractionated radiotherapy over the other altered fractionation radiotherapy schedules direct comparison between altered fractionation radiotherapy and concomitant chemoradiotherapy suggests the superiority of concomitant chemoradiotherapy. Further research is still needed to compare efficacy of hyperfractionated radiotherapy and concomitant chemoradiotherapy