1. Comparison of CTCAE version 3 and 4 for oral mucositis: implications for clinical trials  
Mitchell Hickman
Head and Neck Specialist Radiographer
Queen Elizabeth Hospital, Birmingham, UK.

2. Background
Most oncologists familiar with CTC version 3 for scoring acute mucosal reaction
Recent trials De-Escalate HPV, NIMRAD use CTC version 4
Limited data on correlation of version 4 with version 3
Does this matter?
Despite the technological advancements in radiotherapy, mucositis is debilitating and dose limiting
Version 3 – this is an objective clinical examination of the oral mucosa
Version 4 – which includes subjective variables such as pain, dysphagia and nutritional requirements
A prospective study by Liu et al in 2012 compared both versions for locally advanced nasopharyngeal carcinoma.
23 pts were enrolled in the study - although small numbers they found v3 & v4 produced similar results.
To our knowledge there is no direct comparison for patients with oral or oropharyngeal carcinoma
So, Is the existence of a correlation between v3 & v4 important?

3. Methods Commenced in November 2014
Patients undergoing chemoradiation or radiation alone for oral or oropharyngeal cancer were included
Oral mucosal reactions were graded by three radiation oncologists
CTCAE version 3 and 4 mucositis grading and patient factors were recorded prospectively
The study commenced in November 2014
Patients that were undergoing chemoradiation or radiation alone for oral or oropharyngeal cancer were included
Oral mucosal reactions were graded by three radiation oncologists in weekly on treatment and post treatment clinics
Mucositis grading using both CTC versions was recorded prospectively

4. mild pain not interfering with oral intake
CTC Version
Grade 1 2 3 4
erythema
patchy ulceration
confluent
ulceration
tissue necrosis
no intervention
mild pain not interfering with oral intake
or modified diet
severe pain interfering with oral intake
life threatening urgent intervention
This table shows the difference in the two versions of grading of mucositis.
As previously mentioned Version 3 is a objective assessment graded by the clinician. (Talk through each grade)
Version 4 – g2 – pt would be taking paracetomol
g3 – the pt would require some form of opioid analgesia & or dependent on NGT/PEG
g4 – requiring hospital admission
From the description of each grade there is subjectivity with regards to pain and nutrition

5. Results 555 measurements were recorded in 73 patients
Gradings from version 3 and version 4 were equal in 327 measurements
228 (41%) measurements showed discrepancy between version 3 and 4
Between Nov 2014 and Nov 2015, we collected 555 measurements from 73 patients
Oral mucositis scores were equal in both versions in 327 measurements
But 228 measurements showed discrepancy between version 3 and 4

6. Total measurements (%)
Results: Time
Time from RT Start
Discrepancies/
Total measurements (%) P
(Χ 2 )
Week 0-4
87/205 (42%)
P=0.004
Week 5-8
60/186 (32%)
> Week 8
81/164 (49%)
This table shows when the discrepancy occurred relating to the radiotherapy week. Incidence of discrepancy was predominately seen in the post- treatment period.

7. Results:Time
The Graph shows comparable trajectory of the mean grade of mucositis over a time period for both CTC versions

8. 95% Confidence Intervals
Results: Time (Week 11)
CTC Version
Mean Grade
95% Confidence Intervals 3
2.0
( ) 4
2.5
( )
The anomaly seen at week 11is within the 95% CI and not statistically significant

9. Total measurements (%)
Results-Treatment
Treatment
Discrepancies/
Total measurements (%) P
(Χ 2 )
RT Alone
53/113 (47%)
P<0.001
Synchronous Cetuximab
48/71 (68%)
Synchronous Platinum
127/371 (34%)
Patients were categorized according to treatment received, this was either RT alone, synchronous cetuximab or synchronous platinum.
We can see from the table there was a higher rate of discrepancy between v3 & v4 for those patients receiving cetuximab.
Despite the small number of patients treated with this schedule; this was a significant difference.

10. Results:Cetuximab
And if we look at both CTC versions for cetuximab, grade 3 (which is described as confluent ulceration) on v3 is seen from wk 5,
where as on v4 g3 mucosal toxicity does not spike until after completion of treatment at wk 11

11. Results-Cetuximab v Cisplatin CTC version 3
This slide shows a comparison of cetuximab and cisplatin on v3.
Both drugs seem to be roughly equivalent in the mean grading of mucositis,
but of course this is a non-randomised comparison with small number of pts and is for illustrative purposes only.

12. Results-Cetuximab v Cisplatin CTC version 4
But if we look at v4 we might be lead to believe that cetuximab is associated with less mucosal toxicity due to the subjective nature of v4

13. However both versions produce a similar mean mucosal trajectory
Conclusions
Discrepancy in measure between CTC Version 3 and Version 4 is common (41%)
However both versions produce a similar mean mucosal trajectory
In current small sample no time point identified where there is a significant difference in mean grade of mucositis
So we can conclude, the discrepancy in measurements between CTC V3 & V4 is common, however as previously demonstrated both versions produce a similar mean mucosal trajectory .
In the current small sample of patients, no time point has been identified where there is a significant difference in mean grade of mucositis

14. Conclusions-Problems for Trials
Chemoradiation combinations could produce different results depending on version used if endpoint:
Duration of grade 3 mucositis
Area under mucositis curve
Only analysis of such endpoints as opposed to rate of grade 3 mucositis may reveal true differences in chemort combinations
The study thus far shows Chemoradiation combinations could produce different results depending on the version used if the endpoint was –
Duration of grade 3 mucositis or Area under mucositis curve
The analysis of such endpoints as opposed to rate of grade 3 mucositis may reveal true differences in chemoradiation combinations

15. Conclusions-Problems for Trials
Duration of grade 3 mucositis (version 3) has historically been used as a marker of late mucosal damage
RT+ drug combinations might exist where version 4 underestimates the duration of grade 3 mucositis compared with historical series
Dose escalation studies/Novel RT combinations should use both version 3 and version 4
The Duration of grade 3 mucositis using v3, has historically been used as a marker of late mucosal damage.
Radiotherapy and drug combinations might exist where v4 underestimates the duration of grade 3 mucositis compared with historical series.
Therefore we believe Dose escalation studies and Novel Radiotherapy combinations should use both v3 and v4

16. Conclusions COMPARE STUDY
Treatment escalation in poor and intermediate prognosis oropharynx patients
Mucositis grading using both v3 and v4
>800pts in this study will provide information on the relationship between v3 and v4 and treatment factors
The Compare study is examining treatment escalation in poor and intermediate prognosis oropharyngeal cancers. It will score the grading of mucositis using both CTC versions
The study will recruit in excess of 800 patients and will therefore provide considerable information on the relationship between v3 & v4 and their relationship to treatment factors

17. Thank You