Altered fractionation radiotherapy, especially hyperfractionated radiotherapy, provides improved overall survival compared to conventional fractionation for head and neck cancers. The 2017 MARCH meta-analysis update, which included over 11,000 patients, confirmed the benefits of altered fractionation. Specifically, hyperfractionated radiotherapy resulted in an 8.1% absolute improvement in 5-year survival. Concurrent chemotherapy with conventional radiation was found to be better than altered fractionation alone, but hyperfractionated radiotherapy seems comparable to chemotherapy with standard radiation.

1. CAN WE MARCH WITH MARCH
METAANALYSIS?

2. DR KANHU CHARAN PATRO
The Meta-Analysis of Radiotherapy in squamous
cell Carcinomas of Head and neck (MARCH)
2017 UPDATE
FHNO/ 27th OCT 2018/KOLKATA

3. MARCH: UPDATEDMETA-ANALYSIS
Lancet Oncology 2017

4. DEFINITION OF METAANALYSIS
Meta-analysis is a quantitative approach for
systematically combining results of
previous research to arrive at conclusions
about the body of research.
• Quantitative: numbers
• Systematic: methodical
• Combining: putting together
• Previous research: what's already done
• Conclusions: summary

5. BACKGROUND
1. MARCH (2006) showed that altered
fractionation radiotherapy is associated with
improved overall and progression-free survival
compared with conventional radiotherapy, with
hyperfractionated radiotherapy showing the
greatest benefit.
2. MARCH 2017 aims to confirm and explain the
superiority of hyperfractionated radiotherapy
over other altered fractionation radiotherapy
regimens
A. To assess the benefit of altered fractionation
within the context of concomitant
chemotherapy with the inclusion of new trials.
Altered vs conventional
Altered vs conventional
Altered vs CTRT

6. LEFT BETTER RIGHT BETTER
TOUCHING ISO EFFECT LINE
SMALLER CI
LARGER CI
POOLED ANALYSIS

7. PARAMETERS IN FOREST PLOT

8. DIAMONDS IN METAANALYSIS

9. Conventionalfractionation
• 1.8-2 Gyperfraction
• 1 fraction per day
• 5 fractions per week
• Everything else is altered fractionation!

10. • Conventional fractionation isaconvention, founded
on logistic, ratherthan radiobiological principles
• Various altered fractionation strategies have
developed to exploit the different aspects of
fractionation, asmentioned

11. Graphical

12. Hyperfractionation
• Same/ higher total dose
• Smaller dose/fraction
• Multiple fractions/ day
• Higher number of fractions
• Approximately sameduration
• Rationale=lower late toxicity

13. Acceleratedfractionation
• Same/ lower total dose
• Lower dose/ fraction
• Multiple fractions/day
• Higher number of fractions
• Shorter overall duration
• Rationale=conclusion of radiation coursebefore
onset of acceleratedrepopulation

14. CHART
• Combines the twin advantagesof:
• Hyperfractionation
&
• Accelerated fractionation
• Acommon schedule is 54Gy/36#/12 days

15. Hypofractionation
• Lower total dose
• Higher dose/fraction
• Lessernumber of fraction
• Shorter overall duration

16. PUSHING BACKWARD AND FORWARD AT A TIME
DIFFICULT BUT NOT IMPOSSIBLE
OAR
TARGET
16

17. 1ST MARCH METAANALYSIS
Lancet 2006;368:843–54

18. 1. 15 trials with 6515 patients were
included.
2. Length of follow-up varied from 4 years
to 10 years, with a median of 6 years.
3. Tumors sites mostly oropharynx and
larynx;
4. 74% patients had stage III–IV disease
DETAILS

19. ANALYSIS

20. RESULT
Overall survival
1. Significant OS benefit with
altered fractionated
radiotherapy,
2. An absolute benefit of 3.4%
at 5 years
(HR-0.92 p=0.003).
LOCOREGIONAL CONTROL
ALTERED FRACTIONATION
vs
CONVENTIONAL
(6.4% at 5 years; p<0.0001)
HFRT VS CONV
OS AT 5 YEARS
1. 8% VS 2% without total
dose reduction and
2. 1.7% with total dose
reduction p=0.02)
Age factor
A. (HR- 0.78 for under 50 year )
B. (HR 0.95 for 51–60 year)
C. (HR 0.92 for 61–70 year)
D. (HR 1.08 for over 70 year)

21. MARCH: UPDATEDMETA-ANALYSIS
Lancet Oncology 2017

22. HEAD TO HEAD
SL
NO
PARAMETER 2006 2017
1 NUMBER OF PATIENT 6515 11969
2 NUMBER OF TRIAL 15 34
3 MEDIAN F/UP 6 YR 7.9YR
4 COMPARISION 1. ALT VS CONV 1. ALT VS CONV
2. ALT VS CTRT
5 TOXICITY ANALYSIS NO YES
6 SITES 1. LARYNX
2. HYPOPHARYNX
1. ORAL CAVITY,
2. OROPHARYNX,
3. HYPOPHARYNX
4. LARYNX

23. COMPARISONS 2017
• Comparison 1
– primary or postoperative conventional fractionation
radiotherapy VS altered fractionation radiotherapy.
– CONV. RT VS ALTERED FRACTIONATION RT
• Comparison 2
– Conventional fractionation radiotherapy plus
concomitant chemotherapy versus altered
fractionation radiotherapy alone.
– CONV. RT+CT VS ALTERED FRACTIONATION RT

24. INCLUSION AND EXCLUSION
INCLUSION
• ORAL CAVITY,
• OROPHARYNX,
• HYPOPHARYNX
• LARYNX
EXCLUSION
• NASOPHARYNX
JAN 1st 1970 TO DEC 31st 2010
1. HYPERFRACTIONATED
2. MODERATELY ACCELERATED
3. VERY ACCELERATED
IPD ANALYSIS
34 trials and 11969 patients MEDIAN FOLLOW UP-7.9 years overall

25. MARCH METAANALYSIS 2017 RESULTS
COMPARISION-1
CONV. RT VS ALTERED FRACTIONATION RT
OVERALL SURVIVAL BENEFIT
• HR-0.94 [P=0.0033]
• ABSOLUTE 5 YEAR- 3.1%
• ABSOLUTE 10 YEAR- 1.2%
COMPARISION-2
CONV. RT+CT VS ALTERED FRACTIONATION
OVERALL SURVIVAL BENEFIT
• HR-1.22 [P=0.0098]
• ABSOLUTE 5 YEAR- [-5.8%]
• ABSOLUTE 10 YEAR-[-5.1%]
OVERALL SURVIVAL BENEFIT
• HYPER FRACTIONATED ARM
• HR-0.83 [P=0.0]
• ABSOLUTE 5 YEAR- [8.1%]
• ABSOLUTE 10 YEAR-[3.9%]
1. Altered fractionation radiotherapy is
better than conventional fractionation.
2. Hyperfractionated radiotherapy is better
among all altered fractionation schedules.
3. Concurrent CTRT is better than altered
fractionation.
4. The effect of accelerated radiotherapy is
limited to local control.

26. HYPER FRACTIONATED RT
or
CT+ RT STANDARD
INTERPRETATION
LAHNSC

27. EORTC 2284330

29. EORTC 2284330 Cairo 199047 CRT 90-00246 INRC-HN943
Osaka 199331
INRC-HN-1032
EORTC 2296245
RTOG 951233 ARTSCAN34
IAEA-CRP-ACC35DAHANCA 944
GORTEC 990236
TMH 111437
CHARTWE
pCAIR38RTOG 012939
KROG 020140 POPART41
CONDOR
NEW TRIALS ADDED

30. OS

31. PFS

32. Summary of main results
HYPER-fractionation vsconventional

33. Summary of main results
MOD-ACCELARATED vsconventional

34. Summary of main results
ACCELARATED VS conventional

35. Summary of main results
ALL fractionation VS conventional

36. OVER ALL SURVIVAL

37. OVER ALL SURVIVAL

38. PROGRESSION FREE SURVIVAL

39. PROGRESSION FREE SURVIVAL

40. ACUTE SIDE EFFECTS –
MUCOSITIS IS MORE IN ALTERED

41. LATE SIDE EFFECTS –
FIBROSIS IS MORE IN ALTERED

42. OVERALL SURVIVAL- CTRT VS ALTERED

43. SUBGROUPANALYSIS
13/10/17
•AGE
• No significant interaction between treatment effect on progression- free
survival
• Reduction in treatment effect when age increased for progression- free
survival (p=0.016)
• No interaction between treatment effect on OS or PFS and patient
• Performance status,
• Sex
• Site of primary tumor
• Stage

44. NODE POSITIVE PATIENT
1. In 5592 node positive patients,
2. Found a significant improvement in regional control with altered
fractionation radiotherapy compared with conventional fractionation
3. Significant for hyperfractionated radiotherapy.
4. HR for death was 0.92 (95% CI 0.87–0.96) in the first 5 years after
randomization, and 1.04 (0.93–1.15) beyond 5 years

45. LIT-REVIEW- INDIA-
CTRT vs ALTERD FRACTION
CTRT VS ALTERED
CTRT IS BETTER

46. LIT-REVIEW- INDIA-
CTRT vs ALTERD FRACTION
CTRT AND HYPERFRACTIONATION ARE COMAPREBLE
BUT
ACCELARTED RADIOTHERAPY NOT

48. STRENGTHS
1. Its size- nearly twice as many patients than first
2. IPD analysis
3. Unpublished trials taken to account
4. Longer follow up data
5. Toxicity analysis

49. WEAKNESS
1. Trials included used outdated radiotherapy techniques (2D
AND 3D.(IMRT is the present of care for HNC)
2. In HPV era, these trials often did not record smoking status and
HPV status
3. Further limitation concerns the quality of data collected for the
toxicity analysis.
4. Only 5 trials compared altered fractionation radiotherapy with
standard radiotherapy plus chemotherapy in both groups

50. HOSPITAL
TAKE HOME MESSAGE
1. Altered vs conventional
2. the superiority of hyperfractionated radiotherapy
3. The effect of accelerated radiotherapy is limited to local control.
4. Here as hyperfractionated radiotherapy seems to improve both local and
regional control, and might therefore be preferred for patients with node-
positive tumours.
5. Hyperfractionated radiotherapy or concomitant chemoradiotherapy for the
treatment of locally advanced head and neck cancers may be the standard.
6. Head-to-head comparisons between hyperfractionated.
radiotherapy and concomitant chemoradiotherapy are scarce.