Head and Neck Flashcards
1
Q
What trial help establish PORT dosing?
A
MDACC (Peters et al, IJROBP, 1993, Rosenthal et al, IJROBP, 2017),<div><br></br></div>
2
Q
What is the clinical relevance of the study (MDACC, Peters 1993)?<div><br></br></div>
A
The findings could suggest that dose escalation ≥63 Gy in PORT might be beneficial for ECE at a 2-yr year timepoint, but not at 5 to 20 years (however this interpretation is not endorsed nor addressed in the f/u publication). <br></br><br></br>In PORT,At 5 to 20-yr f/u there is no benefit in LRC with dose escalation from 63 Gy –> 68.4 Gy in the high risk group or 57.6 –> 63 Gy in the low risk group.
3
Q
What was the patient population studied in MDACC PORT trial?
A
“264 with Stage III or IV oral cavity, oropharynx, hypopharynx, larynx<span> who underwent surgery who required post-op RT</span>”
4
Q
What was the regimen studied in MDACC PORT?
A
“Low risk: <br></br>→52.2 Gy or 57.6 (dose changed to 57.6 after excess failures seen with 52.2)<br></br>vs. →63 Gy <br></br><br></br>High risk: <br></br>→63 Gy vs. →68.4 Gy<br></br><br></br>Stratified into low and high risk by a point system now not in use. Head and neck were separately assessed. Any positive margin was high risk. But <span>ECE could be low or high risk based on extent.</span> Other factors: # of nodes, margin distances, sizes.”
5
Q
What were the results of MDACC PORT trial?
A
<div><div><div><div><div>Final report (over 20-yr follow-up): <br></br>20-yr LRC not different<br></br>Factors impacting LRC & OS:</div><div>S->RT completion time ≥85 days, +margin, ECE<br></br>Factor leading to worse OS: age ≥57</div><div><br></br>5-yr LRC 67% <br></br>5-yr DM 36%, 10-yr DM 40%<br></br>5-yr OS 32%, 10-yr OS 20%<br></br>2nd cancers 27%<br></br><br></br><br></br></div></div></div></div></div>
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6
Q
What were the initial results of MDACC PORT?
A
<div><div><div><div><div><div><div><div><br></br>Initial report: 2-yr LF worse with <54 Gy than with ≥ 57.6 Gy. ECE results best with ≥63 Gy. ECE was the only independent risk factor for recurrence. Progressively increased recurrence risk with ≥2 risk factors (oral cavity, close or positive margins, PNI, ≥2 nodes, node ≥3cm, delay >6 wks, low PS)<br></br></div></div></div></div></div><div></div><div></div><div></div></div></div><div></div><div></div></div>
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7
Q
<div>What trial evaluated dose de-escalation in elective nodes?</div>
A
University of Leuven, Belgium<b>(</b>Nevens et al, Radiother Oncol, 2017)
8
Q
What is the clinical relevance of University of Leuven, Belgium (Nevens et al, Radiother Oncol, 2017)
A
Equivalent rates of OS, LF in patient treated elective nodes 50 vs 40 Gy with reduction of salivary toxicity in 40 Gy
9
Q
<div>What was the patient population studied inNevens et al, Radiother Oncol, 2017?</div>
A
“200,<span>Previously untreated </span>head and neck cancer. T1-T2N0 were allowed if elective neck radiation planned”
10
Q
<div>What was the regimen studied inNevens et al, Radiother Oncol, 2017?</div>
A
Noninferiority: <br></br>→50 Gy to elective nodes vs. 40 Gy to elective nodes<br></br><br></br>Doses in normalized effective dose in 2 Gy fractions. 70 Gy in NID 2 Gy per fraction to primary tumor. All patients treated with IMRT
11
Q
<div>What were the results ofNevens et al, Radiother Oncol, 2017trial?</div>
A
Reduction of salivary toxicity with 40 Gy<br></br><br></br>2-yr LF 3.9% in 40 Gy arm, similar to 50 Gy<br></br><br></br>5-yr RR 8% vs. 14%, p=0.10<br></br>5-yr DM 24% vs. 13%, p=0.07<br></br>5-yr OS ~50-55%, not different<br></br><br></br><br></br>
12
Q
Criticisms ofNevens et al, Radiother Oncol, 2017?
A
The trial may be underpowered. The eligibility is T1-T2 and, consequentially, recurrences were low. However, low recurrences in both arms is not a negative thing. Most patients did not undergo neck dissection.<div><br></br></div><div>The trial’s use of iso-effective 2 Gy fractions might lead some to criticize the trial in that its methods are imprecise. However nonstandard doses based on BED calcs are frequently employed in H&N IMRT and this design reflects common techniques (NCCN 2019).</div><div><br></br></div><div>Results may not apply to post op neck since few were included.<br></br><br></br></div>
13
Q
<div>What trial evaluated elective node recurrence following definitive RT?</div>
A
van den Bosch IJROBP, 2016
14
Q
What is the clinical relevance of van den Bosch IJROBP, 2016?
A
Lymph node sum >17mm is risk factor for recurrence. Borderline nodes may be controlled with 60 Gy. 45-50 Gy EQD2 controls elective neck otherwise.
15
Q
<div>What was the patient population studied in van den Bosch IJROBP, 2016?</div>
A
264 H&N cT2-4, N0-2 SCC treated with RT
16
Q
What was the regimen studied in van den Bosch IJROBP, 2016?
A
Retrospective. 1166 lymph nodes localized in elective neck fields and sites of recurrence reconstructed and analyzed based on dose received<br></br><br></br>IMRT SIB accelerated to 68 Gy in 2.00 Gy for boost and 50.3 Gy in 1.48 Gy for elective volume. Last 14 treatments delivered BID.
17
Q
<div>What were the results of van den Bosch IJROBP, 2016 trial?</div>
A
•Elective neck node recurrence 5.1%<br></br>•LN size of 17 mm sum of long and short diameters is risk factor for recurrence<br></br>•Recurrence in nodes usually happens with LR<br></br>•In nodes receiving 60 Gy no recurrences seen
18
Q
What Meta-analysis established altered fractionation superior OS to conventional in head and neck?
A
MARCH-HN
19
Q
What is the clinical relevance of the study MARCH-HN?
A
Altered fractionation gives benefit in OS and LC in head and neck
20
Q
<div>What was the patient population studied in MARCH - HN trial?</div>
A
Meta-analysis of 15 trials11,423 Head and neck definitive and post-op
21
Q
<div>What was the regimen studied in MARCH - HN?</div>
A
“Meta-analysis of 15 trials evaluating the benefit of <span>altered fractionation (defined as either hyperfx</span>, accelerated, or accel with dose reduction) compared to conventional fx<br></br><br></br><span>Update</span>: Meta-analysis of 33 trials<br></br><br></br>Comparison 1: Primary or post op conv fx vs. altered fx<div><br></br>Comparison 2: conv fx chemoRT vs. altered fx RT alone</div>”
22
Q
<div>What were the results of MARCH - HNtrial?</div>
A
5-yr OS benefit of +3.4% with altered fractionation (best benefit with hyperfx, +8%)<br></br>5-yr LC benefit of +6.4%<br></br><br></br>Long term f/u: <br></br>• Compared to primary or post-op conv fx, altered fx benefit in OS: 5-yr +3.1% and 10-yr +1.2%<div><br></br>• OS benefit only in hyperfx group: 5-yr OS +8.1% and 10-yr OS +3.9%<div><br></br>• Compared to conv fx chemo RT, OS worse with hyperfx RT alone, 5-yr OS -5.8% and 10-yr OS -5.1%</div></div>
23
Q
<div>What trial established altered fractionation as standard of care for Stage III-IV if no chemo?</div>
A
RTOG 9003
24
Q
What is the clinical relevance of RTOG 9003?
A
Hyperfrac and accelerated concominant boost result in improved outcomes and lower toxicity than standard fractionation for Stage III-IV without chemo
25
What was the patient population studied in RTOG 9003?
"1073 Stage III-IV (or II for BOT/hypopharynx), previously untreated, to have primary RT"
26
What was the regimen studied in RTOG 9003?
"1) Conventional 70/35 fx in 2Gy
2) Hyperfx 81.6/68 fx in 7 wks in 1.2Gy BID
3) Accel Split: 67.2/42 fx in 6 wks at 1.6Gy BID with 2-wk break at 38.4Gy
4) Accel-con boost: 72Gy/42 fx in 6 wks at 1.8Gy and 1.5Gy
IMRT not allowed"
2) Hyperfx 81.6/68 fx in 7 wks in 1.2Gy BID
3) Accel Split: 67.2/42 fx in 6 wks at 1.6Gy BID with 2-wk break at 38.4Gy
4) Accel-con boost: 72Gy/42 fx in 6 wks at 1.8Gy and 1.5Gy
IMRT not allowed
27
What were the results of RTOG 9003?
Initial: Hyperfrac and delayed concominant boost had better LRC (54%), with trend for better DFS. OS not different.
Update: Hyperfx increased OS, LC when 5 year patients are censored, and decreased late effects. 97% of LR occurred within 5 years. After five years, more second cancers arose though small amounts. Severe late grade 3+ toxicity trended worse for Accel.
Update: Hyperfx increased OS, LC when 5 year patients are censored, and decreased late effects. 97% of LR occurred within 5 years. After five years, more second cancers arose though small amounts. Severe late grade 3+ toxicity trended worse for Accel.
28
Criticisms of RTOG 9003?
Performed before IMRT era. Concurrent chemo was not used. There is criticism that some of the long term results were only significant when data after 5 years was censored.
29
What trial(s) established 6 day/week as standard of care?
IAEA-ACC and DAHANCA 6/7
30
What is the clinical relevance of IAEA-ACC?
For those not receiving chemo, six fractions per week of RT results in better LC and DFS than 5 fractions per week
(This study repeated the DAHANCA regimen but this time without nimorazole)
31
What was the patient population studied in IAEA-ACC?
"1485 glottic, supraglottic pharynx, oral cavity not receiving chemo, eligible for curative RT"
32
What was the regimen studied in IAEA-ACC?
"→5 fx per week
vs.
→6 fx per week
66-70 Gy/ 33-35 fx, no chemo
[no nimorazole as in DAHANCA 6/7]"
vs.
→6 fx per week
66-70 Gy/ 33-35 fx, no chemo
[no nimorazole as in DAHANCA 6/7]"
33
What were the results of IAEA-ACC trial?
"5-yr LRC 42% 6 fx vs. 30% 5 fx
5-yr OS 35% vs. 28%, p=0.07
5-yr DSS 50% vs. 40%
More acute skin and mucositis in accel RT. No difference in late toxicity"
5-yr OS 35% vs. 28%, p=0.07
5-yr DSS 50% vs. 40%
More acute skin and mucositis in accel RT. No difference in late toxicity"
34
What is the clinical relevance of DAHANCA 6 & 7?
For those not receiving chemo, six fractions per week of RT with nimorazole results in better LC and DFS than 5 fractions per week
35
What was the patient population studied in DAHANCA 6 & 7?
"1485 glottic, supraglottic pharynx, oral cavity not receiving chemo, treated with primary RT"
36
What was the regimen studied in DAHANCA 6 & 7?
"→5 fx per week
vs.
→6 fx per week
66-68 Gy/ 33-34 fx, no chemo
Nimorazole for all except for glottic"
vs.
→6 fx per week
66-68 Gy/ 33-34 fx, no chemo
Nimorazole for all except for glottic"
37
What were the results of DAHANCA 6 & 7?
5-yr LRC 70% 6 fx vs. 60% 5 fx
14.5-yr LRF 22% vs. 29%
Larynx preservation 80% vs. 68%
5-yr DSS 73% vs. 66%
No change in OS
Acute morbidity more frequent with 6 fx
14.5-yr LRF 22% vs. 29%
Larynx preservation 80% vs. 68%
5-yr DSS 73% vs. 66%
No change in OS
Acute morbidity more frequent with 6 fx
38
What trial investigated hyperfractionation with chemoRT?
"DAHANCA 28, Saksø et al, Radiother Oncol, 2020"
39
What is the clinical relevance of DAHANCA 28?
This is the first trial to investigate hyperfractionation with chemotherapy with IMRT, and also to ask a fractionation question specifically in HPV negative tumors.
40
What was the patient population studied in DAHANCA 28 trial?
50 HPV negative Stage III-IV H&N cancer
41
What was the regimen studied in DAHANCA 28?
Phase I/II
Hyperfx accel RT 76 Gy/ 56 fx BID with cisplatin + nimorazole
Primary endpoint: LRF
Hyperfx accel RT 76 Gy/ 56 fx BID with cisplatin + nimorazole
Primary endpoint: LRF
42
What were the results of DAHANCA 28 trial?
3-yr LRF 21%
3-yr OS 74%
acute severe dysphagia in 67%
acute severe mucositis in 61%
late severe dysphagia in n=2, severe xerostomia in n=1, severe fibrosis in n=3, osteoradionecrosis in n=1, permanent PEG in n=3
3-yr OS 74%
acute severe dysphagia in 67%
acute severe mucositis in 61%
late severe dysphagia in n=2, severe xerostomia in n=1, severe fibrosis in n=3, osteoradionecrosis in n=1, permanent PEG in n=3
43
Conclusions from DAHANCA 28?
Hyperfx accel RT wih cisplatin and nimorazole is feasible. Although acute toxicity was high, late toxicity seems acceptable.
45
What is the clinical relevance of the study?
Low risk is unlikely to benefit from adjuvant RT.
Int risk benefits from mod dose adjuvant RT.
In high risk there is still opportunity for improvement in LRC.
Int risk benefits from mod dose adjuvant RT.
In high risk there is still opportunity for improvement in LRC.
46
What was the patient population studied in Ang 2001 IJROBP trial?
"288 Post-op H&N
Low risk: 0 factors
Int risk: 1 factor, no ECE
High risk: ECE or >=2 factors
Factors: oral site, PNI, N+, ECE, +margin"
Low risk: 0 factors
Int risk: 1 factor, no ECE
High risk: ECE or >=2 factors
Factors: oral site, PNI, N+, ECE, +margin
47
What was the regimen studied in Ang 2001 IJROBP?
"Low risk - no PORT
Intermediate risk - 57.6 Gy
High risk - randomized:
→63 Gy/5 wks accel
vs.
→63 Gy/7 wks conv + 2 wks CCB"
Intermediate risk - 57.6 Gy
High risk - randomized:
→63 Gy/5 wks accel
vs.
→63 Gy/7 wks conv + 2 wks CCB"
48
What were the results of Ang 2001 IJROBP
trial?
Low Risk: 90% LRC, 83% OS
Int risk: 94% LRC, 66% OS
High Risk: 68% LRC, 42% OS
Trend to higher LRC when RT delivered in 5 vs. 7 weeks for high risk
Int risk: 94% LRC, 66% OS
High Risk: 68% LRC, 42% OS
Trend to higher LRC when RT delivered in 5 vs. 7 weeks for high risk
49
Conclusions from Ang 2001 IJROBP?
Time <11 weeks gave better survival and LRC
50
What trials established addition of chemo to post-op RT for ENE/+margins as standard of care?
51
What is the clinical relevance of EORTC 22931 and RTOG 9501
The addition of chemo to adjuvant RT improves OS and LRC in post-op H&N tumors with risk factors ushc as ENE/+margins
52
What was the patient population studied in EORTC 22931 trial?
334 pts T3-4 (except larynx T3N0), T1-2N2-3, T1-2N0 with ENE +M PNI or LVI, OC or OPX with level IV or V nodes
53
What was the regimen studied in EORTC 22931?
"→Post-op RT 66 Gy (54 Gy to low risk) vs.
same RT + cisplatin x3"
same RT + cisplatin x3"
54
What were the results of EORTC 22931 trial?
"5-yr PFS 36% vs. 47%
5-yr OS 40% vs. 53%
3-yr OS 49% vs. 65%
5-yr LRC 69% vs. 82%"
5-yr OS 40% vs. 53%
3-yr OS 49% vs. 65%
5-yr LRC 69% vs. 82%"
55
What was the patient population studied in RTOG 9501 trial?
459 pts operable H+N with ≥2 N+, ENE, or + margin
56
What was the regimen studied in RTOG 9501?
"→Post-op RT 60 Gy ± 6 Gy boost vs.
same RT + cisplatin x3"
same RT + cisplatin x3"
57
What were the results of RTOG 9501 trial?
"2-yr LRC 72% vs. 82%, p=0.01
5-yr LRC 11% vs. 13%
2-yr OS 57% vs. 63%, p=0.19
5-yr OS 12% vs. 13%
For positive margins or ECE:
10-yr LRC 67% vs. 79%
10-yr OS 20% vs. 27%"
5-yr LRC 11% vs. 13%
2-yr OS 57% vs. 63%, p=0.19
5-yr OS 12% vs. 13%
For positive margins or ECE:
10-yr LRC 67% vs. 79%
10-yr OS 20% vs. 27%"
58
What doses do RTOG 9501 and EORTC 22931 use?
What doses did the two trials use? EORTC used 66 Gy (Bernier 2004), and although RTOG used a base dose of 60 Gy, a 6 Gy boost was allowed to total 66 Gy
59
What trials established addition of chemo to post-op RT as standard of care in certain cases?
EORTC 22931(Bernier), RTOG 9501 (Cooper)
60
What is the clinical relevance of EORTC 22931?
The addition of chemo to adjuvant RT improves OS and LRC in post-op H&N tumors with risk factors.
61
What is the clinical relevance of RTOG 9501?
The addition of chemo to adjuvant RT improves OS and LRC in post-op H&N tumors with risk factors.
62
What was the patient population studied in EORTC 22931?
334 T3-4 (except larynx T3N0), T1-2N2-3, T1-2N0 with ENE +M PNI or LVI, OC or OPX with level IV or V nodes
63
What trial established concurrent chemoradiation as standard of care?
MACH-NC
64
What is the clinical relevance of MACH-NC?
Meta-analysis confirms an OS benefit with the addition of concurrent chemotherapy to RT in H&N tumors. Concurrent has greater benefit than induction.
65
What was the patient population studied in MACH-NC trial?
17,346 pts H&N SCC trials comparing local treatment with chemo or without
66
What were the results of MACH-NC?
"Chemo (all forms of sequencing) had an absolute 5-yr OS benefit of +4.5%. If concurrent chemo, 5-yr OS benefit is +8%."
67
What trial established addition of cetuximab to RT in non-cisplatin patients?
"University Alabama Birmingham, Bonner et al, NEJM, 2006"
68
What is the clinical relevance of the Bonner trial?
Adding cetuximab to RT improves LC and OS.
69
What was the patient population studied in Bonner trial?
414 pts Stage III or IV nonmetastatic SCC of oropharynx, hypopharynx, or larynx
70
What was the regimen studied in Bonner trial?
→RT with concurrent cetuximab
vs.
→RT alone
RT conventional 70 Gy, or hyperfrac 72-76.8 Gy/ 1.2 BID, or CCB 72 Gy/ 42 fx
vs.
→RT alone
RT conventional 70 Gy, or hyperfrac 72-76.8 Gy/ 1.2 BID, or CCB 72 Gy/ 42 fx
71
What were the results of Bonner trial?
Median LC 24 vs. 15 mos
2-yr LC 50% vs 41%
median OS 49 vs. 29 mos
3-yr OS 55% vs 45%. Acneiform rash and infusion reactions more common, but otherwise not more toxic.
OS for grade 2-4 acneiform rash 69 mos vs 25 without
2-yr LC 50% vs 41%
median OS 49 vs. 29 mos
3-yr OS 55% vs 45%. Acneiform rash and infusion reactions more common, but otherwise not more toxic.
OS for grade 2-4 acneiform rash 69 mos vs 25 without
73
What is the clinical relevance of Brizel et al?
CRT with split course improves outcomes over hyperfrac RT without chemo.
74
What was the patient population studied in Brizel trial?
116 pt T3-4 cancers or T2N0 BOT
75
What was the regimen studied in Brizel et al?
→75 Gy hyperfx, 1.2 Gy BID
vs.
→concurrent RT cis/5FU (split 1 wk RT break at 40 Gy) → adj cis/5FU
vs.
→concurrent RT cis/5FU (split 1 wk RT break at 40 Gy) → adj cis/5FU
76
What were the results of Brizel trial?
CRT improved 3-yr LC from 44% to 70%
RFS 61 vs. 41%. p=0.08
3-yr OS 34% vs. 55%, p=0.07
adverse effects similar
RFS 61 vs. 41%. p=0.08
3-yr OS 34% vs. 55%, p=0.07
adverse effects similar
77
What trial established evaluated concurrent chemo versus split course?
"INT, Adelstein et al, JCO, 2003"
78
What is the clinical relevance of Aldestein et al?
Concurrent chemo improves OS with increase in toxicity. The benefit was lost when chemo was added to split course RT.
79
What was the patient population studied in Adelstein et al trial?
295 pts Unresectable oral cavity, oropharynx, larynx, or hypopharynx
80
What was the regimen studied in Adelstein et al?
→70 Gy alone
vs.
→70 Gy + concurrent cisplatin x 3
vs.
→split-course 70 Gy + cis/5-FU
vs.
→70 Gy + concurrent cisplatin x 3
vs.
→split-course 70 Gy + cis/5-FU
81
What were the results of Aldestein et al trial?
Continuous CRT improved 3-yr OS (37% vs. RT 23% vs. split-course plus chemo 27%) and DFS, but increased Gr 3-4 toxicity
82
What trial suggested benefit of induction chemo ?
"GSTTC Italian Study Group, Ghi et al, Ann Oncol, 2017"
83
What is the clinical relevance of GSTTC Italian Study Group?
"Induction chemo improves OS, PFS, LRC, and CR and maintains compliance with chemoRT. On subanalysis the best effect was with concurrent cetuximab.
Given the history of other negative inducation trials, results should be interpreted with caution."
Given the history of other negative inducation trials, results should be interpreted with caution."
84
What was the patient population studied in GSTTC Italian Study Group trial?
414 pt locally advanced, Stage III-IV AJCC V, nonmetastatic SCC
unresectable or low suitability for surgery
unresectable or low suitability for surgery
85
What was the regimen studied in GSTTC Italian Study Group?
→induction TPF
vs.
→no induction
→conc cis/5FU
vs.
→conc cetuximab
2x2 randomization
vs.
→no induction
→conc cis/5FU
vs.
→conc cetuximab
2x2 randomization
86
What were the results of GSTTC Italian Study Group trial?
"Induction chemo improved OS, PFS, LRC, and CR
Median OS induction 55 vs. 32 mos
3-yr OS 58% vs. 47%
CR 43% vs. 28%
median PFS 31 mos vs. 19 mos
DM ~15%, not different
-On subanalysis, better effect with conc cetuximab and non-OPX site, but underpowered
-More febrile neutropenia with induction
-ChemoRT breaks not different"
Median OS induction 55 vs. 32 mos
3-yr OS 58% vs. 47%
CR 43% vs. 28%
median PFS 31 mos vs. 19 mos
DM ~15%, not different
-On subanalysis, better effect with conc cetuximab and non-OPX site, but underpowered
-More febrile neutropenia with induction
-ChemoRT breaks not different"
87
Hypothesis on why Italian study positive for induction where other studies negative?
Perhaps HPV epidemiology played role; prevalence may be higher in US and lower in this study. The trials had slightly different regimens. Perhaps cetuximab somehow sensitizes better when delivered after induction chemo as the subanalysis suggests (but this is contradictory to the lower HPV prevalence idea), or perhaps the concurrent chemo is overtreatment. It is unclear what population, if any, truly benefits from induction chemo. Refer also to RTOG 9111, where on long term follow-up the induction chemo arm (with no concurrent chemo) trended to better OS.
Given the other 3 negative trials, results should be interpreted with caution. Patient characteristics seemed well balanced. HPV was not assessed in the trial's era. RT was 70 Gy with ≥60 Gy to neck.
Given the other 3 negative trials, results should be interpreted with caution. Patient characteristics seemed well balanced. HPV was not assessed in the trial's era. RT was 70 Gy with ≥60 Gy to neck.
88
What trials showed negative results of induction chemotherapy?
DeCIDE, PARADIGM, Madrid study
89
What is the clinical relevance of Paradigm/Decide/Madrid?
"No benefit to induction chemotherapy. Toxicity is increased."
90
What was the patient population studied in DeCIDE trial?
285 pts N2 or N3 SCC of H&N
91
What was the regimen studied in DeCIDE?
→Induction TPF, RT + conc THF
vs.
→RT + conc THF
H=hydroxyurea. RT to 74-75 Gy hyperfx
vs.
→RT + conc THF
H=hydroxyurea. RT to 74-75 Gy hyperfx
92
What were the results of DeCIDE trial?
"-No benefit in 30-mos OS, RFS, or DMFS
-Mortality ~30% in both arms
-Serious adverse events more common in induction arm 47% vs. 28%
-In the induction group, 122/124 completed RT"
-Mortality ~30% in both arms
-Serious adverse events more common in induction arm 47% vs. 28%
-In the induction group, 122/124 completed RT"
93
What was the patient population studied in PARADIGM trial?
145 unresectable, low surgical curability T3/T4, N2/3 (but not T1N2), or organ preservation
94
What was the regimen studied in PARADIGM?
→Induction TP, RT + conc carbo or docetaxol
vs.
→RT + conc cis
If poor response to induction: 72 Gy RT in 6 weeks with docetaxel
If favorable response: 70 Gy RT in 7 weeks with carboplatin AUC 1.5
vs.
→RT + conc cis
If poor response to induction: 72 Gy RT in 6 weeks with docetaxel
If favorable response: 70 Gy RT in 7 weeks with carboplatin AUC 1.5
95
What were the results of PARADIGM trial?
"No benefit in OS or PFS
3-yr OS ~75% and 3-yr PFS ~68%
-Serious adverse events in 52 vs. 22 pts
-Grade 3-4 mucositis 47% vs. 16%
-More febrile neutropenia with induction
-RT breaks similar, 6 vs. 5 pts
-Terminated due to slow accrual"
3-yr OS ~75% and 3-yr PFS ~68%
-Serious adverse events in 52 vs. 22 pts
-Grade 3-4 mucositis 47% vs. 16%
-More febrile neutropenia with induction
-RT breaks similar, 6 vs. 5 pts
-Terminated due to slow accrual"
96
What was the patient population studied in Madrid trial?
439 unresectable, Stage III-IV AJCC V, nonmetastatic SCC
97
What was the regimen studied in Madrid trial?
→Induction TPF, RT + conc cis
vs.
→induction PF, RT + conc cis
vs.
→RT + conc cis
vs.
→induction PF, RT + conc cis
vs.
→RT + conc cis
98
What were the results of Madrid trial?
"No change in PFS, TTF, or OS
Median PFS ~14 mos, TTF 8 mos, OS 27 mos
-More neutropenia, odynophagia, stomatitis with induction chemo
-With induction 113/155 completed RT compared to 118/128 in RT alone arm"
Median PFS ~14 mos, TTF 8 mos, OS 27 mos
-More neutropenia, odynophagia, stomatitis with induction chemo
-With induction 113/155 completed RT compared to 118/128 in RT alone arm"
99
What trial established noninferiority of PET vs neck dissection?
"PET-NECK, Mehanna et al, NEJM, 2016"
100
What is the clinical relevance of PET-NECK?
"OS is noninferior with neck dissection guided by PET vs. planned dissection in all. "
101
What was the patient population studied in PET-NECK trial?
564 N2 or N3 SCC of H&N
102
What was the regimen studied in PET-NECK?
"Noninferiority
→chemoRT then PET in 3 mos then neck dissection only if incomplete or equivocal response
vs.
→planned neck dissection"
→chemoRT then PET in 3 mos then neck dissection only if incomplete or equivocal response
vs.
→planned neck dissection"
103
What were the results of PET-NECK trial?
Surgical complications 42% vs. 38%
2-yr OS 84.9% vs. 81.5%
HR for death slightly favored PET and indicated noninferiority
2-yr OS 84.9% vs. 81.5%
HR for death slightly favored PET and indicated noninferiority
104
What trial evaluated ommision of RT to dissected N0 neck?
"Washington University, Contreras et al, JCO, 2019"
105
What is the clinical relevance of the Contreas study?
Control of uninvolved neck is 97% with ispilateral RT when omitting RT in the dissected N0 neck.
106
What was the patient population studied in Contreas trial?
72 H&N s/p surgery and neck dissection with a pN0 neck with indications for adjuvant RT. T1-2N0-2b ipsilateral tonsil was excluded.
107
What was the regimen studied in Contreas study?
Phase II. Omits RT to dissected N0 neck
IMRT SIB to 66/54 Gy or 60/52 Gy. Chemo as indicated.
IMRT SIB to 66/54 Gy or 60/52 Gy. Chemo as indicated.
108
What were the results of Contreras trial?
"Control of uninvolved dissected neck 97%
Those that failed also failed at primary
5-yr LC 84%, RC 93%, PFS 60%, OS 64%
Characteristics: 59% N2-3, 51% T3-4, 71% crossed midline, 34% had chemo"
Those that failed also failed at primary
5-yr LC 84%, RC 93%, PFS 60%, OS 64%
Characteristics: 59% N2-3, 51% T3-4, 71% crossed midline, 34% had chemo"
109
Questions about applicability of Contreras study?
This study was performed in a single institution, Wash U. Is it applicable to all? Wash U typically performs high quality resections and extensive neck dissections. Note that this study included any pN0 neck, not necessarily the contralateral neck. For example, applying this data could allow one to exclude RT to the neck in pT4N0 larynx and treat primary site only. In this study dissection to the N0 neck is required. Another interesting question would be whether RT is required in a cN0 undissected neck. Which is more toxic: dissection or RT to the contralateral neck? If neck dissection can be omitted when RT is done, there could possibly be less toxicity. Practices vary. Refer also to nodal guidelines (Biau 2019.)
111
What is the clinical relevance of ACRIN 6685?
PET negative cN0 neck can provide confidence that a neck dissection will be negative, especially with lower SUV.
112
What was the patient population studied in ACRIN 6685 trial?
268 neck sides, H&N cancer with at least one cN0 neck that was planned for dissection, PET
113
What was the regimen studied in ACRIN 6685?
"Prospective
PET → negative cN0 neck → dissection of that neck and evaluation of node status"
PET → negative cN0 neck → dissection of that neck and evaluation of node status"
114
What were the results of ACRIN 6685 trial?
"-PET in cN0 neck was true negative in 87% after dissection
-If max SUV <3.5 in neck, NPV was 94%, specific to each node level
-PET changed decisions in 22%"
-If max SUV <3.5 in neck, NPV was 94%, specific to each node level
-PET changed decisions in 22%"
115
What trial evaluated omiting RT to tonsil primary post op bed?
"U Penn Swisher-McClure et al, IJROBP, 2019"
116
"What is the clinical relevance of the UPenn Swisher-McClure et al, IJROBP, 2019? "
Control of tonsil post-op bed is 98% when omitting RT to this area when indications to treat the primary are not present while treating the neck with RT.
117
What was the patient population studied in UPenn trial?
60 tonsil HPV+ SCC pT1-pT2 N1-3 s/p TORS
118
What was the regimen studied in UPenn Study?
Omit RT to resected tonsil post-op bed if no indications to treat primary, and RT to neck with indications to treat neck
119
What were the results of UPenn trial?
2-yr primary LC 98.3% (n=1 recurrence)
2-yr regional recurrence 1.7%
2-yr DM 3.3%
Mean RT dose to primary 39.6 Gy
2-yr regional recurrence 1.7%
2-yr DM 3.3%
Mean RT dose to primary 39.6 Gy
120
What trials established IMRT to avoid xerostomia as standard of care?
GORTEC 2004-01, RTOG 0022, PARSPORT
121
What is the clinical relevance of GORTEC 2004-01, RTOG 0022, PARSPORT?
IMRT reduces xerostomia
122
What was the patient population studied in GORTEC 2004-01 trial?
188 locally advanced H&N SCC
123
What was the regimen studied in GORTEC 2004-01?
→70 Gy/ 35 fx 3DCRT
vs.
→75 Gy/ 35 fx IMRT
50 Gy then sequential boost in both arms
Concurrent cisplatin in both
vs.
→75 Gy/ 35 fx IMRT
50 Gy then sequential boost in both arms
Concurrent cisplatin in both
124
What were the results of GORTEC 2004-01 trial?
1-yr grade ≥2 xerostomia 63% vs. 23%
3-yr grade ≥2 xerostomia 45% vs. 11%
LR and OS not different
3-yr grade ≥2 xerostomia 45% vs. 11%
LR and OS not different
125
What was the patient population studied in RTOG 0022 trial?
69 oropharynx T1-2, N0-1
126
What was the regimen studied in RTOG 0022?
"IMRT SIB 66/60-54 in 30 fx. No chemo"
127
What were the results of RTOG 0022 trial?
Xerostomia 6 mos 55%, 1 year 25%, 2 years 16%. Grade 2 reactions: salivary 67%, skin 12%, mucosa 24%, esophagus 19%. Salivary output did not improve over time. 2-yr LRC 91%
128
Unique fact about RTOG 0022?
This trial established a sometimes used dose regimen for SIB IMRT. Though some advocate caution using 220 cGy per fraction.
129
What was the patient population studied in PARSPORT trial?
47 pharynx SCC T1-T4, N0-N3
130
What was the regimen studied in PARSPORT?
"60 or 65 Gy/ 30 fx parotid sparing IMRT
vs.
conventional RT"
vs.
conventional RT"
131
What were the results of PARSPORT trial?
IMRT improved xerostomia
12-mo xerostomia 38% vs 75%
24-mo xerostomia grade ≥2 29% vs 83%
QOL scores
12-mo xerostomia 38% vs 75%
24-mo xerostomia grade ≥2 29% vs 83%
QOL scores
132
What trial established Larynx preservation as standard of care?
VALSG (VA Larynx Study Group)
133
What is the clinical relevance of the VA Larynx Study?
Larynx preservation feasible and maintains OS outcomes.
Long-term QOL is superior with preservation.
Long-term QOL is superior with preservation.
134
What was the patient population studied in VA Larynx trial?
332 Stage III-IV (not T1N1)
135
What was the regimen studied in VA Larynx Study?
"→total laryngectomy + post-op RT (50-70 Gy)
vs.
→induction 3 cycles PF → 70 Gy if CR or PR. If no response: surgery+post-op RT"
vs.
→induction 3 cycles PF → 70 Gy if CR or PR. If no response: surgery+post-op RT"
136
What were the OS, LF, DM results of VA Larynx trial?
"No difference in 2-yr OS. CRT had worse LF but improved DM
2-yr OS 68%, not different
LF 12% vs. 2%
RF 8% vs. 5% (NS)
DM 11% vs. 17%, p=0.04
"
2-yr OS 68%, not different
LF 12% vs. 2%
RF 8% vs. 5% (NS)
DM 11% vs. 17%, p=0.04
137
What was the rate of larynx preservation in VA Larynx trial?
2-yr larynx preservation 64%.
-Long term QOL is improved with chemoRT. Better freedom from pain, emotional well being, less depression
138
What trial established Concurrent chemoRT as standard of care in Larynx?
139
What is the clinical relevance of the RTOG 9111?
On long term f/u there is trend to worse OS with concurrent CRT but overall no statistically significant change in OS. Concurrent chemoRT resulted in improved LRC and larynx preservation.
140
What was the patient population studied in RTOG 9111 trial?
"547 Stage III-IV glottic or supraglottic (excluded extension through thyroid cartilage, large volume T4a, and >1 cm BOT involvment. Limited T4 was allowed) who would otherwise had required total laryngectomy
69% of patients were supraglottic"
69% of patients were supraglottic"
141
What was the regimen studied in RTOG 9111?
"→RT with concurrent cis 5FU x3
vs.
→induction cis/5FU → RT (VA regimen)
vs.
→RT alone 70 Gy "
vs.
→induction cis/5FU → RT (VA regimen)
vs.
→RT alone 70 Gy "
142
What were the 2 yr results of RTOG 9111 trial?
"2-yr larynx sparing 88% vs. 75 vs. 70%
2-yr LRC 78% vs. 61% vs. 56%
"
2-yr LRC 78% vs. 61% vs. 56%
"
143
What were the long term follow up results of RTOG 9111?
"Concurrent chemoRT improved larynx preservation. At long term f/u OS trends to better with induction over concurrent.
10-yr larynx sparing 82% vs. 68% vs. 64%
10-yr LC 69% vs. 54% vs. 50%
Long term f/u:
Deaths not attributed to larynx cancer worse with concurrent:
31% vs. 21% vs. 17%
Trend to better OS with induction (p=0.08 vs. concurrent)
10-yr OS 28% vs. 39% vs. 32% (NS)
10-yr DM 16% vs. 16% vs. 24%
<3% with inability to swallow"
10-yr larynx sparing 82% vs. 68% vs. 64%
10-yr LC 69% vs. 54% vs. 50%
Long term f/u:
Deaths not attributed to larynx cancer worse with concurrent:
31% vs. 21% vs. 17%
Trend to better OS with induction (p=0.08 vs. concurrent)
10-yr OS 28% vs. 39% vs. 32% (NS)
10-yr DM 16% vs. 16% vs. 24%
<3% with inability to swallow"
144
What trial established larynx preservation in hypopharyngeal cancer as standard of care?
"EORTC 24891, Lefebvre et al, JNCI, 1996
Lefebvre et al, Ann Oncol, 2012"
Lefebvre et al, Ann Oncol, 2012"
145
What is the clinical relevance of EORTC 24891?
Larynx preservation with induction chemo for hypopharynx yields outcomes comparable to surgery. However, overall outcomes are still poor.
146
What was the patient population studied in EORTC 24891 trial?
202 SCC of pyriform sinus or AE fold
147
What was the regimen studied in EORTC 24891?
"→surgery + post-op RT
vs.
→induction cis/5FU → RT if CR
(surgery for PR)
[Similar to VA trial]"
vs.
→induction cis/5FU → RT if CR
(surgery for PR)
[Similar to VA trial]"
148
What were the results of EORTC 24891 trial?
"LF trend to higher with RT. Trend to less DM with chemo
3-yr larynx preservation 42%,
5-yr larynx preservation 35%
5-yr OS 33%, not different
10-yr OS ~13.5%, not different
10-yr chemoRT survival with functional larynx 8.7%
"
3-yr larynx preservation 42%,
5-yr larynx preservation 35%
5-yr OS 33%, not different
10-yr OS ~13.5%, not different
10-yr chemoRT survival with functional larynx 8.7%
149
What trial(s) established TPF as induction chemo for larynx preservation as standard of care?
"GORTEC 2000-01, Pointreau et al, JNCI, 2009
"
"
150
What is the clinical relevance of GORTEC 2000-01?
TPF resulted in superior response rates compared to PF in larynx sparing in hypoharynx cancer.
151
What was the patient population studied in GORTEC 2001-01 trial?
220 larynx or hypopharynx T3-T4 primary sites or T2 not appropriate for partial laryngectomy, requiring total laryngectomy
152
What was the regimen studied in GORTEC 2000-01?
→Induction TPF x3
vs.
→Induction PF
→ RT 70 Gy for CR or PR.
If no response, total laryngectomy and RT 54-66 Gy
vs.
→Induction PF
→ RT 70 Gy for CR or PR.
If no response, total laryngectomy and RT 54-66 Gy
153
What were the results of GORTEC 2000-01 trial?
Increased laryngeal preservation in TPF arm
3-yr laryngeal preservation 70% vs 58%
10-yr larynx preservation 70% vs 47%
10-yr larynx dysfunction free survival 64% vs. 37%
Response rates 80% vs 59%
More grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia with TPF, and more stomatitis and thrombocytopenia with PF
3-yr laryngeal preservation 70% vs 58%
10-yr larynx preservation 70% vs 47%
10-yr larynx dysfunction free survival 64% vs. 37%
Response rates 80% vs 59%
More grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia with TPF, and more stomatitis and thrombocytopenia with PF
154
Induction for Laryngeal cancer?
Although the PARADIGM, DECIDE, and Spanish trials showed no benefit to induction chemo in overall H&N, could there still be some utility in larynx? (Haddad 2013, Cohen 2014, Hitt, 2014). In RTOG 9111 long term f/u showed a trend toward reduced survival with concurrent chemo compared to induction (Forastierre 2003).
155
What trial compared RT vs surgery in early stage larynx?
"Helsinki University Central Hospital, Finland, Aaltonen et al, IJROBP, 2014"
156
What is the clinical relevance of Aaltonen et al?
"RT seems to provide superior voice outcomes compared to surgery for early stage larynx cancer."
157
What was the patient population studied in Aaltonen et al trial?
60 T1a larynx
158
What was the regimen studied in Aaltonen et al?
"→66 Gy
vs.
→CO2 laser
blinded experts rated voice quality on GRBAS scale, patient self-assessed voice quality and ADL impact, and blinded videostrobe"
vs.
→CO2 laser
blinded experts rated voice quality on GRBAS scale, patient self-assessed voice quality and ADL impact, and blinded videostrobe"
159
What were the results of Aaltonen et al trial?
"Overall similar voice quality. CO2 laser group had wider glottal gap and more breathy voice. RT group had less hoarseness related inconvenience at 2 years (p=0.007). 3 patients in each group recurred"
160
What trial established hypofractionation as standard of care in early larynx?
161
What is the clinical relevance of the Yamazaki study?
Hypofractionation with 2.25 Gy per fraction shows superior local control over 2 Gy per fraction.
162
What was the patient population studied in Yamazaki et al trial?
180 T1N0 glottic
163
What was the regimen studied in Yamazaki et al?
2 Gy vs. 2.25 Gy fractions:
Minimal tumors (≤2/3 vocal cord) 60Gy vs. 56.25Gy
Larger tumors 66Gy vs. 63Gy
Minimal tumors (≤2/3 vocal cord) 60Gy vs. 56.25Gy
Larger tumors 66Gy vs. 63Gy
164
What were the results of Yamazaki et al trial?
5-yr LC 77% vs. 92% for 2.25 Gy/fx
No difference in 5-yr CSS or toxicity
No difference in 5-yr CSS or toxicity
165
What trial showed unilateral treatment of well lateralized early T stage oral cavity?
"University of Queensland, Brisbane, Australia, Liu et al, ASTRO, 2018"
166
"What is the clinical relevance of Liu et al? "
In well-lateralized early T stage oral cavity, unilateral treatment is associated with low risk of contralateral failures.
167
What was the patient population studied in Liu et al trial?
"176 well lateralized T1-2 N0-2b oral cavity s/p surgery & unilateral neck dissection ± RT to primary ± RT to unilateral neck
Excluded bilateral neck treatment, ECE, +margin, chemo"
Excluded bilateral neck treatment, ECE, +margin, chemo"
168
What were the results of Lui et al?
5-yr bilateral or contralateral neck failures in 4.3%
17% had RT, 68% T1, and 55% N0
17% had RT, 68% T1, and 55% N0
169
What trial established neck dissection in oral cavity as standard of care?
"Tata Memorial Centre, Mumbai, D'Cruz et al, NEJM, 2015"
170
"What is the clinical relevance of D'Cruz et al, NEJM, 2015? "
"Elective neck dissection results in improved DFS and OS."
171
What was the patient population studied in D' Cruz trial?
596 T1-2N0 oral cavity SCC
172
What was the regimen studied in D'Cruz?
"Resection then
→ipsilateral neck dissection
vs.
→obs (LND for recurrence)"
→ipsilateral neck dissection
vs.
→obs (LND for recurrence)"
173
What were the results of D'Cruz trial?
OS 80% vs. 68%
DFS 70% vs. 46%
Some suggestion of benefit with DOI >3 mm, p=0.12
DFS 70% vs. 46%
Some suggestion of benefit with DOI >3 mm, p=0.12
174
What trial showed SLNB equivalent to neck dissection in early stage oral caivty?
"Senti-MERORL, Garrel et al, JCO, 2020"
175
What is the clinical relevance of Senti-MERORL?
"SLNB and neck dissection are equivalent in early stage SCC. SLNB is preferred."
176
What was the patient population studied in Senti-MERORL trial?
307 T1-2N0 oral cavity SCC
177
What was the regimen studied in Senti-MERORL?
"Equivalence:
Resection then
→ipsilateral neck dissection
vs.
→SLNB and LND if positive"
Resection then
→ipsilateral neck dissection
vs.
→SLNB and LND if positive"
178
What were the results of Senti-MERORL trial?
2-yr neck RFS 90% vs. 91%
(equivalent)
(equivalent)
179
What trial established concurrent chemoRT in orophaynx as standard of care?
"University of Queensland, Brisbane, Australia, Denis et al, IJROBP, 2003"
180
"What is the clinical relevance of Denis et al, IJROBP, 2003? "
The addition of concurrent chemo improves LC and OS without increase in late toxicity in oropharynx.
181
"
What was the patient population studied in Denis et al, IJROBP, 2003 trial?
"
226 Stage III/IV oropharynx
182
"
What was the regimen studied in Denis et al, IJROBP, 2003?
"
→70 Gy with carbo/5-FU x3
vs.
→RT alone
vs.
→RT alone
183
"
What were the results of Denis et al, IJROBP, 2003 trial?
"
"CRT improved 5-yr LC 48% vs. 25%
5-yr DFS 27% vs. 15%
5-yr OS 22% vs. 16%, increased acute but not late toxicity"
5-yr DFS 27% vs. 15%
5-yr OS 22% vs. 16%, increased acute but not late toxicity"
184
What trial compared conventional fractionation with chemo versus accleterated RT?
"GORTEC 99-02, Bourhis et al, Lancet, 2012"
185
What is the clinical relevance of GORTEC 99-02?
"Conventional fractionation with chemo results in superior OS and lower toxicity compared to accelerated RT."
186
What was the patient population studied in GORTEC 99-02 trial?
559 Stage III or IV SCC
187
What was the regimen studied in GORTEC 99-02?
1) RT 70 Gy/7 weeks with carbo/5FU
2) Acc RT 70 Gy/6 weeks (2 Gy daily for 40 Gy then 1.5 BID) with carbo/5FU/
3) Very Acc RT 64.8 Gy/3.5 weeks, no chemo
2) Acc RT 70 Gy/6 weeks (2 Gy daily for 40 Gy then 1.5 BID) with carbo/5FU/
3) Very Acc RT 64.8 Gy/3.5 weeks, no chemo
188
What were the results of GORTEC 99-02 trial?
"Slight improvements with conventional RT
3-yr OS 43% Conv vs. 39% vs. 37%
3-yr LFR 42% vs. 45% vs. 50%
3-yr DM 25% vs. 34% vs. 28% (NS)
G3-4 mucosal toxicity 69% vs. 76% vs. 84%
Feeding tube 60% vs. 64% vs. 70%, "
3-yr OS 43% Conv vs. 39% vs. 37%
3-yr LFR 42% vs. 45% vs. 50%
3-yr DM 25% vs. 34% vs. 28% (NS)
G3-4 mucosal toxicity 69% vs. 76% vs. 84%
Feeding tube 60% vs. 64% vs. 70%, "
189
What trial established risk stratification of HPV+ oropharynx?
"RTOG 0129 Ang et al, NEJM, 2010
"
"
190
What is the clinical relevance of RTOG 0129?
Analyzed standard chemoRT versus accelerated chemoRT. Found There is no difference in LRF, PFS, OS, DM, and toxicity in AFX-CB vs. standard RT.
Also established HPV risk stratification
191
What was the patient population studied in RTOG 0129 trial?
323 Stage III-IV SCC or oral cavity, oropharynx, hypopharyx, or larynx
192
What was the regimen studied in RTOG 0129?
→Standard RT 70 Gy with cisplatin
vs.
→accelerated fractionation with concominant boost (AFX-CB) 72 Gy in 6 weeks concurrent cis
vs.
→accelerated fractionation with concominant boost (AFX-CB) 72 Gy in 6 weeks concurrent cis
193
What were the results of RTOG 0129 trial?
"3-yr OS HPV+/HPV-: 82% vs. 57%
3-yr DM HPV+/HPV-: 9% vs. 15%
3-yr LRC HPV+/HPV-: 86% vs. 65%
For RT regimens, No difference in 8-yr OS, PFS, LRF, DM, or toxicity"
3-yr DM HPV+/HPV-: 9% vs. 15%
3-yr LRC HPV+/HPV-: 86% vs. 65%
For RT regimens, No difference in 8-yr OS, PFS, LRF, DM, or toxicity"
194
What was the 3yr OS in different risk gorups in RTOG 0129?
3-yr OS by RPA group (see commentary for classes):
Low risk: 93%
Int risk: 71%
High risk: 46%
Low risk: 93%
Int risk: 71%
High risk: 46%
196
What is the clinical relevance of ORATOR?
QOL results are demonstrated. RT resulted in superior 1-yr dysphagia scores but not to a clinically meaningful degree.
197
What was the patient population studied in ORATOR trial?
"68 Oropharynx T1-2, N0-1 or N2b (up to two nodes ≤3cm) HPV+/-
88% were HPV+"
88% were HPV+"
198
What was the regimen studied in ORATOR?
Phase II
TORS and neck dissection [71% had post-op RT] vs. RT with or without chemotherapy
TORS and neck dissection [71% had post-op RT] vs. RT with or without chemotherapy
199
What were the results of ORATOR trial?
The study shows that dyshagia QOL with radiation is at least as good as TORS. ORATOR2 will also measure more QOL points and other outcomes (NCT03210103).
200
What trial compared concurrent cisplatin versus cisplatin +cetuximab?
RTOG 0522
201
What is the clinical relevance of RTOG 0522?
Adding cetuximab to RT and cisplatin did not improve outcomes.
202
What was the patient population studied in RTOG 0522 trial?
891 oropharynx Stage III or IV
203
What was the regimen studied in RTOG 0522?
concurrent cisplatin+cetuximab vs. cisplatin
AccCB/IMRT
AccCB/IMRT
204
What were the results of RTOG 0522 trial?
No diff in 3 yr OS (76% vs. 73%) or PFS (59% vs. 61%). With cetuximab, mucositis and skin reactions worse.
205
What study evaluated ipsilateral neck radiation in tonsil?
"Princess Margaret Hospital, O'Sullivan et al, IJROBP, 2001
Huang et al, IJROBP, 2017"
Huang et al, IJROBP, 2017"
206
What is the clinical relevance of the O'Sullivan study?
Ispilateral neck radiation in tonsil cancer T1-T2N1-N2b results in excellent control.
There is no difference per HPV status.
There is no difference per HPV status.
207
What was the patient population studied in Princess Margaret Hospital study?
228 Ipsilateral tonsil, no surgery
208
What was the regimen studied in Princess Margaret Hospital study?
Retrospective. RT only to ipsilateral side, no chemo
209
What were the results of Princess Margaret Hospital study?
"-Contralateral failure: T1 0%, T2 1.5%, T3 10%, T4 0%, N0 0%, N1 9%, N2/3 0%.
-Sig risk for failure if involving medial one third of palate, BOT
-No difference in LC or RC for HPV+ vs. HPV- in 379 patients from 1999-2014"
-Sig risk for failure if involving medial one third of palate, BOT
-No difference in LC or RC for HPV+ vs. HPV- in 379 patients from 1999-2014
210
What trials evaluated Cetuximab vs. Cisplatin in HPV + oropharynx?
211
What is the clinical relevance of RTOG 1016?
"Cetuximab with RT resulted in inferior OS and PFS compared to cisplatin in HPV+ oropharynx. Toxicity is not reduced with cetuximab."
212
What was the patient population studied in RTOG 1016 trial?
849 HPV+ locally advanced oropharynx p16+. T1-2 N2a-3 or T3-4, and N
213
What was the regimen studied in RTOG 1016?
"→RT 70 Gy in 6 weeks (DAHANCA) SIB 56 & 52.5 Gy with concurrent
cisplatin
vs.
→cetuximab"
cisplatin
vs.
→cetuximab"
214
What were the results of RTOG 1016?
"5-yr OS 85% vs. 78%
5-yr PFS 78% vs. 67%
5-yr LRF 10% vs. 17%
5-yr DM 9% vs. 12%
Severe and acute toxicity similar"
5-yr PFS 78% vs. 67%
5-yr LRF 10% vs. 17%
5-yr DM 9% vs. 12%
Severe and acute toxicity similar"
215
What is the clinical relevance of the De-Escalate study?
"Cetuximab with RT resulted in inferior OS and LC compared to cisplatin in HPV+ oropharynx. Toxicity is not reduced with cetuximab."
216
What was the patient population studied in De-Escalate trial?
304 Stage III-IV (T3N0, T4N0, T1N1-T2N3) HPV+ oropharynx cancer. Excludes N2b, N2c, >10 PY
217
What was the regimen studied in De-Escalate?
→70 Gy in 6 weeks with
cisplatin
vs.
→cetuximab
cisplatin
vs.
→cetuximab
218
What were the results of De-Escalate trial?
2-yr OS 98% vs. 89%
2-yr any recurrence 16% vs. 6%
Severe and any grade toxicity similar
2-yr any recurrence 16% vs. 6%
Severe and any grade toxicity similar
219
What trial evaluated chemoRT versus RT alone in Oropharynx HPV+ T1-2, N1-2b, or T3,N0-2b and <10 PY?
"NRG HN002, Yom et al, ASTRO, 2019"
220
What is the clinical relevance of NRG HN002?
60 Gy IMRT+cisplatin met the pre-determined criteria for further study. Cisplatin should not be removed.
221
What was the patient population studied in NRG HN002 trial?
296 Oropharynx HPV+ T1-2, N1-2b, or T3,N0-2b and <10 PY
222
What was the regimen studied in NRG HN002?
Phase II
→60 Gy IMRT with weekly cis
vs.
→60 Gy alone
Endpoint: PFS >85%
→60 Gy IMRT with weekly cis
vs.
→60 Gy alone
Endpoint: PFS >85%
223
What were the results of NRG HN002 trial?
IMRT+cis: 2-yr PFS 91%, p=0.035
IMRT: 2-yr PFS 88%, p=0.088%, CI extends below 85%
Dsyphagia scores acceptable in both arms
IMRT: 2-yr PFS 88%, p=0.088%, CI extends below 85%
Dsyphagia scores acceptable in both arms
224
What is NRG HN005 studying?
"Oropharynx HPV+ T1-3, N1, and <10 PY (AJCC 8)
→70 Gy in 6 weeks (DAHANCA) + cisplatin
vs.
→60 Gy/ 30 fx + cisplatin
vs.
→60 Gy/ 30 fx + nivolumab
"
vs.
→60 Gy/ 30 fx + cisplatin
vs.
→60 Gy/ 30 fx + nivolumab
225
What trial studied HPV+ post-op intermediate risk RT dose?
"EGOC 3311, Ferris et al, ASCO, 2020"
226
What is the clinical relevance of the ECOG 3311?
"All approaches led to favorable outcomes in HPV+ oropharynx.
TORS and adjuvant 50 Gy RT for intermediate risk warrants comparison to chemoRT in a phase III trial.
TORS and adjuvant 50 Gy RT for intermediate risk warrants comparison to chemoRT in a phase III trial.
Phase II
TORS →
• Low risk (negative margins, no ECE, 0-1 nodes):
-observed
• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):
-50 Gy vs. 60 Gy
• High risk (>1 mm ENE, positive margins, or ≥5 nodes):
-66 Gy RT weekly cisplatin
"
TORS →
• Low risk (negative margins, no ECE, 0-1 nodes):
-observed
• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):
-50 Gy vs. 60 Gy
• High risk (>1 mm ENE, positive margins, or ≥5 nodes):
-66 Gy RT weekly cisplatin
227
What was the patient population studied in ECOG 3311 trial?
377 Resectable oropharynx cancer stage III-IV, p16+, who undergo TORS
228
What was the regimen studied in ECOG 3311?
"Phase II
TORS →
• Low risk (negative margins, no ECE, 0-1 nodes):
-observed
• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):
-50 Gy vs. 60 Gy
• High risk (>1 mm ENE, positive margins, or ≥5 nodes):
-66 Gy RT weekly cisplatin "
TORS →
• Low risk (negative margins, no ECE, 0-1 nodes):
-observed
• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):
-50 Gy vs. 60 Gy
• High risk (>1 mm ENE, positive margins, or ≥5 nodes):
-66 Gy RT weekly cisplatin "
229
What were the results of ECOG 3311 trial?
2-yr PFS
Low risk: 94%
Int risk (50 Gy vs. 60 Gy): 95% vs. 96%
High risk: 91%
Low risk: 94%
Int risk (50 Gy vs. 60 Gy): 95% vs. 96%
High risk: 91%
230
What is PATHOS trial studying?
"Oropharynx cancer stage II-III (T1-T3, N0-2b, <10 PY), p16+, who undergo TORS
Intermediate risk: 50 Gy IMRT vs. 60 Gy
High risk: 60 Gy IMRT vs. 60 Gy with weekly cisplatin
"
High risk: 60 Gy IMRT vs. 60 Gy with weekly cisplatin
231
What is EORTC 1420-HNCG-ROG studying?
"Oropharynx Stage I/II HPV+/-
TORS and neck dissection
vs. RT
"
vs. RT
232
What is ORATOR2 studying?
"T1-2, N0-2, p16 +/-
TORS and neck dissection
vs.
RT with or without chemotherapy
"
vs.
RT with or without chemotherapy
234
"What is the clinical relevance of Zhang et al,?"
Induction chemo and concurrent chemo should be recommended in nasopharynx cancer. Adjuvant chemo should be avoided.
235
What was the patient population studied in Zhang el al trial?
8036 Nasopharynx
236
What was the regimen studied in Zhang el al?
Meta-analysis of 28 randomized trials to evaluate benefit of neoadjuvant, concurrent, and adjuvant chemo
Trial sequence approach and fixed or random effects model
Trial sequence approach and fixed or random effects model
237
What were the results of Zhang el al trial?
Induction chemo improves OS, PFS, DM, and LRC
Concurrent chemo improves OS, PFS, DM, and LRC
Adjuvant chemo did not improve outcomes
Concurrent chemo improves OS, PFS, DM, and LRC
Adjuvant chemo did not improve outcomes
239
What is the clinical relevance of MAC-NPC?
There is an OS benefit with concurrent chemotherapy in nasopharynx. There is no benefit with adjuvant and induction.
240
What was the patient population studied in MAC-NPC trial?
8221 Nasopharynx
All subtypes
All subtypes
241
What was the regimen studied in MAC-NPC?
Meta-analysis of 28 trials
2 outlier trials were excluded
2 outlier trials were excluded
242
What were the results of MAC-NPC trial?
Induction with taxane gave best OS when evaluating individual types of chemo
When combining all types of chemo, adjuvant chemo had better OS than induction
When combining all types of chemo, adjuvant chemo had better OS than induction
243
What trial established concurrent and adjuvant chemo as standard of care?
244
What is the clinical relevance of INT 0099?
Concurrent and adjuvant chemo added to RT results in OS benefit in nasopharynx.
245
What was the patient population studied in INT 0099 trial?
193 Stage III-IV (would include some current T2)
246
What was the regimen studied in INT 0099?
"→70 Gy
vs.
→70 Gy + concurrent cisplatin x3 & adj cisplatin 5FU x3"
vs.
→70 Gy + concurrent cisplatin x3 & adj cisplatin 5FU x3"
247
What were the results of INT 0099 trial?
"3-yr OS 78% vs. 47%. PFS 69% vs. 24%
5-yr OS 67% vs 37%, PFS 58% vs 29%"
5-yr OS 67% vs 37%, PFS 58% vs 29%"
249
"What is the clinical relevance of Lee et al, Cancer, 2020?"
Induction chemotherapy with PX may improve PFS and OS compared to adjuvant chemotherapy with conventionally fractionated RT.
250
"
What was the patient population studied in Lee et al, Cancer, 2020 trial?
"
803 nasopharynx Stage III-IVB, nonkeratinizing
251
"
What was the regimen studied in Lee et al, Cancer, 2020?
"
6 arms:
1) adj PF, conventional RT
2) ind PF, conventional RT
3) ind PX, conventional RT
4) adj PF, 6 fx weekly RT
5) ind PF, 6 fx weekly RT
6) ind PX, 6 fx weekly RT
1) adj PF, conventional RT
2) ind PF, conventional RT
3) ind PX, conventional RT
4) adj PF, 6 fx weekly RT
5) ind PF, 6 fx weekly RT
6) ind PX, 6 fx weekly RT
252
"
What were the results of Lee et al, Cancer, 2020 trial?
"
No difference with RT regimens
Overall, no difference in induction/adj
On exploratory analysis, some difference with induction/adj with conventional RT only:
5-yr PFS 78% vs. 62%
5-yr OS 84% vs. 72%
better PFS with PX over PF induction
5-yr PFS 78% vs. 62%
Overall, no difference in induction/adj
On exploratory analysis, some difference with induction/adj with conventional RT only:
5-yr PFS 78% vs. 62%
5-yr OS 84% vs. 72%
better PFS with PX over PF induction
5-yr PFS 78% vs. 62%
253
What trials established concurrent chemoRT in nasopharynx as standard of care?
Taichung Veterans Hospital, Taiwan
Sun Yat-sen University, Guangzhou, China
254
What is the clinical relevance of the Taichung Veterans Hospital, Taiwan study?
Concurrent chemo added to RT results in improved OS.
255
What was the patient population studied in Taichung Veterans Hospital, Taiwan trial?
284 Stage III-IV M0
WHO grade I-III
WHO grade I-III
256
What was the regimen studied in Taichung Veterans Hospital, Taiwan?
→70-74 Gy
vs.
→70-74 Gy with concurrent cisplatin 5FU
vs.
→70-74 Gy with concurrent cisplatin 5FU
257
What were the results of Taichung Veterans Hospital, Taiwan trial?
5-yr OS 54% vs 72%
5-yr PFS 53% vs 72%
5-yr PFS 53% vs 72%
258
What is the clinical relevance of the Sun Yat-sen University, Guangzhou, China study?
Concurrent chemo added to RT results in improved OS, PFS, DMFS, and LRC.
259
What was the patient population studied in Sun Yat-sen University, Guangzhou, China trial?
230 T1-2N1 or T2N0 with parapharyngeal involvement, WHO grade II-III
260
What was the regimen studied in Sun Yat-sen University, Guangzhou, China?
→68-70 Gy alone
vs.
→68-70 Gy with weekly cisplatin
vs.
→68-70 Gy with weekly cisplatin
261
What were the results of Sun Yat-sen University, Guangzhou, China trial?
Chemo RT improved OS, PFS, DMFS, LRC:
5-yr OS 86% vs 95%
5-yr LRC 91% vs 93%
5-yr PFS 78% vs 88%
5-yr DMFS 84% vs 95%
5-yr OS 86% vs 95%
5-yr LRC 91% vs 93%
5-yr PFS 78% vs 88%
5-yr DMFS 84% vs 95%
262
What trial showed no benefit to adjuvant chemo in nonkeritinizing nasopharynx?
"Sun Yat-sen University, Guangzhou, China, Chen et al, Lancet Oncol, 2012"
263
"What is the clinical relevance of the Chen et al, Lancet Oncol, 2012 study? "
There is no benefit to adjuvant chemotherapy.
264
"
What was the patient population studied in Chen et al, Lancet Oncol, 2012 trial?
"
251 Stage III/IV (not T3 or T4)
nonkeratinizing
nonkeratinizing
265
"
What was the regimen studied in Chen et al, Lancet Oncol, 2012?
"
RT to ≥66 Gy in 2.0-2.27 Gy / fx with concurrent weekly cisplatin →
adjuvant cisplatin 5FU x3
vs. no adjuvant
adjuvant cisplatin 5FU x3
vs. no adjuvant
266
"
What were the results of Chen et al, Lancet Oncol, 2012 trial?
"
2-yr FFS 86% vs 84%, p=0.13
2-yr OS 94% vs 92%, p=0.32
2-yr DMS 88% vs 86%, p=0.12
2-yr LRFFS 98% vs 95%, p=0.10
2-yr OS 94% vs 92%, p=0.32
2-yr DMS 88% vs 86%, p=0.12
2-yr LRFFS 98% vs 95%, p=0.10
267
What studies showed benefit of induction chemo in nasopharynx?
"Sun Yat-sen University, Guangzhou, ChinaSun et al, Lancet Oncol, 2016
Sun Yat-sen University, Guangzhou, China Zhang et al, NEJM, 2019
"
268
"What is the clinical relevance of the Sun et al, Lancet Oncol, 2016 study? "
Addition of induction TPF to chemoRT improved FFS. Longer term follow-up is needed.
269
"
What was the patient population studied in Sun et al, Lancet Oncol, 2016 trial?
"
241 Stage III-IVB
nonkeratinizing
nonkeratinizing
270
"
What was the regimen studied in Sun et al, Lancet Oncol, 2016?
"
→Induction TPF then RT with cisplatin
vs.
→chemoRT alone
vs.
→chemoRT alone
271
"
What were the results of Sun et al, Lancet Oncol, 2016 trial?
"
3-yr FFS 80% vs 72%
Grade 3-4 neutropenia 42% vs 7%
Grade 3-4 leucopenia 41% vs 17%
Grade 3-4 stomatitis 41% vs 35%
Grade 3-4 neutropenia 42% vs 7%
Grade 3-4 leucopenia 41% vs 17%
Grade 3-4 stomatitis 41% vs 35%
272
"What is the clinical relevance of the Zhang et al, NEJM, 2019 study? "
Induction chemo added to chemoRT improves RFS and OS compared to no induction chemo.
273
"
What was the patient population studied in Zhang et al, NEJM, 2019 trial?
"
480 Stage IIIB-IVB
nonkeratinizing
nonkeratinizing
274
"
What was the regimen studied in Zhang et al, NEJM, 2019?
"
gem/cis induction vs. no induction prior to chemoRT
RT to 66-70 Gy/ 30-33 fx with concurrent cisplatin
RT to 66-70 Gy/ 30-33 fx with concurrent cisplatin
275
"
What were the results of Zhang et al, NEJM, 2019 trial?
"
3-yr RFS 85% vs. 77%
3-yr OS 95% vs. 90%
acute grade 3-4 toxicity 76% vs. 56%
late grade 3-4 toxicity 9% vs. 11%
3-yr OS 95% vs. 90%
acute grade 3-4 toxicity 76% vs. 56%
late grade 3-4 toxicity 9% vs. 11%
276
What trial showed no benefit of induction for nasopharynx?
"National Cancer Centre Singapore, Singapore Tan et al, IJROBP, 2015 "
277
"What is the clinical relevance of the Tan et al, IJROBP, 2015? "
There is no benefit to induction chemotherapy in nasopharynx cancer.
278
"
What was the patient population studied in Tan et al, IJROBP, 2015 trial?
"
172 Nasopharynx
WHO II-III
WHO II-III
279
"
What was the regimen studied in Tan et al, IJROBP, 2015?
"
→RT with concurrent weekly cisplatin
vs.
→induction gem/carbo/paclitaxel x2 with chemoRT
vs.
→induction gem/carbo/paclitaxel x2 with chemoRT
280
"What were the results of Tan et al, IJROBP, 2015?
"
"
No difference in 3-yr OS, 92% GCP vs 94%.
No difference in DFS or DMFS
After GCP, more dose de-intensification of cis were required
No difference in DFS or DMFS
After GCP, more dose de-intensification of cis were required
281
What trial established treated of primary of nasopharynx in metastatic setting as standard of care?
"Sun Yat-sen University You et al, JAMA Oncol, 2020"
282
"What is the clinical relevance of You et al, JAMA Oncol, 2020? "
Locoregional treatment in metastatic nasopharynx cancer improves OS and reduces DM.
283
"
What was the patient population studied in You et al, JAMA Oncol, 2020 trial?
"
126 Metastatic nasopharynx cancer with CR or PR after PF x3
(only 1.5% were keratininzing)
(only 1.5% were keratininzing)
284
"
What was the regimen studied in You et al, JAMA Oncol, 2020?
"
PF x3, then if CR or PR→
→PF x6 then 70 Gy IMRT to primary
vs.
→PF x6
Primary endpoint: OS
→PF x6 then 70 Gy IMRT to primary
vs.
→PF x6
Primary endpoint: OS
285
"
What were the results of You et al, JAMA Oncol, 2020 trial?
"
2-yr OS 76% C+RT vs. 55% chemo
2-yr DM 54% vs 68%
2-yr PFS 35% vs. 4%
About 70% had ≥3 metastases
2-yr DM 54% vs 68%
2-yr PFS 35% vs. 4%
About 70% had ≥3 metastases
286
What is NRG-HN001 studying?
"Stage II-IVB with detectable EBV DNA
RT with concurrent cisplatin, then test EBV DNA. Then
if detectable EBV, then consolidation 5-FU/cisplatin x3 vs gem/paclitaxel x4
if undetectable EBV, then consolidation 5-FU/cisplatin x3 vs obs
"
if detectable EBV, then consolidation 5-FU/cisplatin x3 vs gem/paclitaxel x4
if undetectable EBV, then consolidation 5-FU/cisplatin x3 vs obs
287
What trial established IMRT of nasopharynx as standard of care?
RTOG 0225
288
What is the clinical relevance of RTOG 0225?
"Outcomes with this IMRT SIB regimen are improved over Intergroup 0099."
289
What was the patient population studied in RTOG 0225 trial?
68 Nasopharynx Stage I-IVB
290
What was the regimen studied in RTOG 0225?
"IMRT to 70 Gy/59.4 Gy in 33 fx. For ≥T2b or N+: concurrent cisplatin and adjuvant cis/5FU"
291
What were the results of RTOG 0225 trial?
"2 yr LC 92%, 2 yr OS 80%, 2-yr regional PFS 91%, 2-yr DMF 86%
acute grade 4 mucositis 4%, late grade 3 dysphagia 5%, xerostomia 3%, long term PEG 4%"
acute grade 4 mucositis 4%, late grade 3 dysphagia 5%, xerostomia 3%, long term PEG 4%"
292
What study evaluated ChemoRT versus observation following salvage surgery after recurrence?
"GETTEC/GORTEC Janot et al, JCO, 2008
"
"
293
"What is the clinical relevance of the Janot et al, JCO, 2008 study? "
"Salvage chemoRT improves DFS but not OS compared to no treatment. Toxicity can be significant."
294
"
What was the patient population studied in Janot et al, JCO, 2008?
"
130 Recurrent or 2nd primary H&N cancer in a previously irradiated area
295
"
What was the regimen studied in Janot et al, JCO, 2008?
"
Salvage surgery then:
→Obs
vs.
→60 Gy in 11 weeks with concurrent 5FU and hydroxyurea
→Obs
vs.
→60 Gy in 11 weeks with concurrent 5FU and hydroxyurea
296
"
What were the results of Janot et al, JCO, 2008?
"
DFS significantly improved with RT with HR of 1.68, but OS not significantly different. Grade 3-4 late toxicity was 39% vs. 10% with obs.
297
What trial established fesability of chemoRT in recurrence of HN?
"RTOG 9610 Spencer et al, Head Neck, 2008"
298
What is the clinical relevance of RTOG 9610?
ChemoRT for recurrent H&N cancer is feasible with acceptable adverse effects.
299
What was the patient population studied in RTOG 9610?
"86 Recurrent SCC or ""second primary"" in prev irradiated field, unresectable. RT finished >6 mos prior"
300
What was the regimen studied in RTOG 9610?
Phase II. RT to 60 Gy in 1.5 Gy BID per fx
3DCRT allowed. Chemo with 5FU/hydroxyurea.
3DCRT allowed. Chemo with 5FU/hydroxyurea.
301
What were the results of RTOG 9610 trial?
2 yr-OS 15%, 5-yr OS 5%. Better survivial if >1 year interval from recurrence. F/u 16 months
Acute grade 4 in 18%, grade 5 in 8%. Late grade 3-4 toxicity 9%
Acute grade 4 in 18%, grade 5 in 8%. Late grade 3-4 toxicity 9%
302
What study looked at reirradiation of recurrent HN?
"MIRI Collaborative Caudell et al, IJROBP, 2017"
303
What is the clinical relevance of the MIRI Collaborative study?
Hyperfx and elective neck RT did not improve outcomes and may worsen toxicity. RT to a dose of ≥66 Gy improved OS and LRF.
304
What was the patient population studied in MIRI Collaborative?
505 Recurrent H&N undergoing reirradiation with IMRT
305
What were the results of MIRI Collaborative?
Elective neck RT and hyperfx did not improve LRF or OS.
≥66 Gy improved OS and LRF.
Dose did not obviously affect outcomes in post-op reirradiation.
Highest rates of late toxicity in hyperfx and post-op RT.
≥66 Gy improved OS and LRF.
Dose did not obviously affect outcomes in post-op reirradiation.
Highest rates of late toxicity in hyperfx and post-op RT.
