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.

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?

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

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

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

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.

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

95% Confidence Intervals Results: Time (Week 11) CTC Version Mean Grade 95% Confidence Intervals 3 2.0 (1.7-2.3) 4 2.5 (2.1-2.9) The anomaly seen at week 11is within the 95% CI and not statistically significant

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.

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

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.

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

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

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

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

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

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