The document discusses the long-term follow-up results of the RTOG 9501/Intergroup Phase III trial, which evaluated postoperative concurrent radiation therapy and chemotherapy for high-risk squamous cell carcinoma of the head and neck. It highlights inclusion criteria, trial design, treatment compliance, and outcomes such as locoregional control, disease-free survival, and overall survival. Although concurrent treatment showed some benefits in specific circumstances, longer-term follow-up suggested diminishing advantages compared to radiation therapy alone, with an increase in late toxicities observed.

1. Long-term Follow-up of the RTOG
9501/Intergroup Phase III Trial: Postoperative
Concurrent Radiation Therapy and
Chemotherapy in High-Risk Squamous Cell
Carcinoma of the Head and Neck

2. Introduction
● In the 1990s two randomized clinical trials
were conducted looking at the role of
concurrent chemoradiation after surgery in
LAHNCC
– RTOG 9501 (Blue)
– EORTC 22931 (Yellow)
● Publications discusses results at long term
FU.

3. Inclusion Criteria (RTOG / EORTC)
● High Risk LAHNSCC
– ≥ 2 Involved Nodes
– ECE
– Positive mucosal
margin
* No stage as inclusion /
exclusion criteria
● T3 – T4 with any N (except
T3N0 Larynx)
● T1-2 with N2-3
● T1-2 with N0-1 with high risk
features:
– ECE
– PNI
– LVE
– Positive Margins
– Level IV-V involement in oral
cavity / oropharyngeal cancers

4. Inclusion Criteria

5. Inclusion Criteria
● KPS 60 or more
● TLC > 3500
● PLT > 100000
● Cr Clearance > 50
● Age 18 – 70
● PS : 0 – 2
● TLC > 4000
● PLT > 100000
● AST/ALT/Bil < 2 ULN
● Creatinine < 1.36

6. Radiotherapy & Chemotherapy
● Time: Within 56 days
● Dose : 60 Gy in 30 #
● Optional Boost : 6 Gy
●
CDDP 100 mg/m2
D1, D22, D43
● Time : ?
● Dose:
– Ph I: 54 Gy in 27 #
– Ph II: 12 Gy in 6 #
(Boost to areas with high
risk of tumor
dissemination / close
margins)
●
CDDP : 100 mg/m2
D1,
D22 and D43

7. Trial Design
● Control Arm : 2 year
LC 38%
● Absolute
Improvement of 15%
● Total No: 438
(assuming 10%
attrition)
● Control Arm : 3 year
PFS 40%
● Absolute
Improvement of 15%
● Total No: 338

8. Study Endpoints
● Locoregional Control
(1º) – LF / RF or
both.
● DFS
● OS
● Adverse Effects
● PFS (1º) – Any type of
progression or death.
● OS
● Local/Regional Failure
● Distant Metastasis
● 2nd Cancers
● Adverse Events

9. Baseline Characteristics
● 459 patients
● Female: 14%
● Median Age: 55
● > 70 Yrs : 7%
● +ve Margin alone: 6%
● ECS alone: 49%
● ECS &/ Margin : 59%
● 334 Patients
● Female : 7%
● Median Age : 54
● > 70 Yrs : 0%
● +ve Margin alone : 13%
● ECS alone : 41%
● ECS &/ Margin : 70%

10. Baseline Characteristics
● Oral Cavity: 28%
● Oropharynx: 42%
● Hypopharynx: 10%
● Larynx: 20%
● Oral Cavity: 26%
● Oropharynx: 30%
● Hypopharynx: 20%
● Larynx: 22%

11. Baseline Characteristics
● PD Tumors: 33%
● T3/4 Tumors: 61%
● N2-3: 94%
? Influence of HPV
● PD Tumors: 19%
● T4 Tumors: 66%
● N2-3 Tumors: 57%

12. Treatment Compliance
● Specific Sx: 97%
● Delay (> 62
days):1%
● Inadequate RT: 20%
● Inadequate CT: 17%
● Specific Sx : NA
● Delay (> 56
days):7%
● Inadequate RT: 29%
● Inadequate CT: 36%*
* Doesnot include dose reductions /
delays

13. Loco Regional Relapse
● 5 year LRF :
– 19% (CRT)
– 30% (RT) *
● 10 year LRF:
– 22% (CRT)
– 28% (RT)
* Crude Rates
● 5 Year LRF :
– 18% CRT
– 31% RT*

14. Loco Regional Relapse

15. DFS/PFS
● 5 year DFS:
– HR : 0.78 *
● 10 year DFS:
– 20.1 (CRT)
– 19.1 (RT)
– HR : 0.88
● 5 year PFS:
– 36% (RT)
– 47% (CRT) *
– HR : 0.75

16. OS
● 5 year OS:
– HR : 0.84
● 10 year OS:
– 29% (CRT)
– 27% (RT)
– HR : 0.89
● 5 year OS:
– 40% (RT)
– 53% (CRT) *
– HR : 0.70

17. OS Curves

18. Combined EORTC/RTOG Analysis
● Points of difference (RTOG vs EORTC):
– More oropharyngeal cancers
– Less hypopharyngeal cancers
– More number N2-N3 disease
– More number PD tumors
– However only 59% of patients had ECE &/or +ve
margins as compared to 70% in EORTC !!

19. Combined EORTC/RTOG Analysis
Implication : Number of nodes involved and T stage as well as level of node
involved are not important predictive factors that result in benefit from CRT.

20. New RTOG Analysis
● In ECE / +ve Margins RT alone resulted in :
– 10 Year LRR increased from 21% to 31%
– 10 year DFS decreased from 18% to 12%
– 10 year OS decreased from 27% to 19%
● These differences were not seen when ECE &
or +ve margins were absent.
● No significant differences by the number of
nodes involved.

21. Causes of Failure
RT CRT

22. OS by Cause of Death

23. Late Toxicity
● Grade 3 – 5 late
toxicity developed in
25% CRT vs 20% RT
patients
● Grade IV toxicity:
7.3% for CRT vs
3.7% for RT
●

24. Conclusions
● Longer term followup has blunted the benefits
that CRT provides above RT
– However benefit in DFS / LRC in ECE/+ve
margins persist
● Late toxicity increased
– However with time increased incidence not seen
● CRT did not appear to benefit in multiple
nodes.