Head and Neck Flashcards
What trial help establish PORT dosing?
MDACC (Peters et al, IJROBP, 1993, Rosenthal et al, IJROBP, 2017),<div><br></br></div>
What is the clinical relevance of the study (MDACC, Peters 1993)?<div><br></br></div>
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.
What was the patient population studied in MDACC PORT trial?
“264 with Stage III or IV oral cavity, oropharynx, hypopharynx, larynx<span> who underwent surgery who required post-op RT</span>”
What was the regimen studied in MDACC PORT?
“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.”
What were the results of MDACC PORT trial?
<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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What were the initial results of MDACC PORT?
<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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<div>What trial evaluated dose de-escalation in elective nodes?</div>
University of Leuven, Belgium<b>(</b>Nevens et al, Radiother Oncol, 2017)
What is the clinical relevance of University of Leuven, Belgium (Nevens et al, Radiother Oncol, 2017)
Equivalent rates of OS, LF in patient treated elective nodes 50 vs 40 Gy with reduction of salivary toxicity in 40 Gy
<div>What was the patient population studied inNevens et al, Radiother Oncol, 2017?</div>
“200,<span>Previously untreated </span>head and neck cancer. T1-T2N0 were allowed if elective neck radiation planned”
<div>What was the regimen studied inNevens et al, Radiother Oncol, 2017?</div>
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
<div>What were the results ofNevens et al, Radiother Oncol, 2017trial?</div>
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>
Criticisms ofNevens et al, Radiother Oncol, 2017?
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>
<div>What trial evaluated elective node recurrence following definitive RT?</div>
van den Bosch IJROBP, 2016
What is the clinical relevance of van den Bosch IJROBP, 2016?
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.
<div>What was the patient population studied in van den Bosch IJROBP, 2016?</div>
264 H&N cT2-4, N0-2 SCC treated with RT
What was the regimen studied in van den Bosch IJROBP, 2016?
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.
<div>What were the results of van den Bosch IJROBP, 2016 trial?</div>
•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
What Meta-analysis established altered fractionation superior OS to conventional in head and neck?
MARCH-HN
What is the clinical relevance of the study MARCH-HN?
Altered fractionation gives benefit in OS and LC in head and neck
<div>What was the patient population studied in MARCH - HN trial?</div>
Meta-analysis of 15 trials11,423 Head and neck definitive and post-op
<div>What was the regimen studied in MARCH - HN?</div>
“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>”
<div>What were the results of MARCH - HNtrial?</div>
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>
<div>What trial established altered fractionation as standard of care for Stage III-IV if no chemo?</div>
RTOG 9003
What is the clinical relevance of RTOG 9003?
Hyperfrac and accelerated concominant boost result in improved outcomes and lower toxicity than standard fractionation for Stage III-IV without chemo
<div>What was the patient population studied in RTOG 9003?</div>
“1073 Stage III-IV (or II for BOT/hypopharynx), previously untreated, <span>to have primary RT</span>”
<div>What was the regimen studied in RTOG 9003?</div>
“1) Conventional 70/35 fx in 2Gy<br></br><br></br>2) <span>Hyperfx 81.6/68 fx in 7 wks in 1.2Gy BID</span><br></br><br></br>3) Accel Split: 67.2/42 fx in 6 wks at 1.6Gy BID with 2-wk break at 38.4Gy<br></br> <br></br>4) <span>Accel-con boost: 72Gy/42 fx in 6 wks at 1.8Gy and 1.5Gy</span><div><span><br></br></span>IMRT not allowed</div>”
<div>What were the results of RTOG 9003?</div>
Initial: Hyperfrac and delayed concominant boost had better LRC (54%), with trend for better DFS. OS not different. <br></br><br></br>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.
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.<br></br>
<div>What trial(s) established 6 day/week as standard of care?</div>
<div>IAEA-ACC and DAHANCA 6/7</div>
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<div><br></br></div><div>(This study repeated the DAHANCA regimen but this time without nimorazole)</div>
What was the patient population studied in IAEA-ACC?
“1485 glottic, supraglottic pharynx, oral cavity <span>not receiving chemo</span>,<span> eligible for curative RT</span>”
What was the regimen studied in IAEA-ACC?<br></br>
“<span><span>→5 fx per week<br></br>vs. <br></br></span>→6 fx per week<span><br></br><br></br> 66-70 Gy/ 33-35 fx, no chemo</span><br></br>[no nimorazole as in DAHANCA 6/7]</span>”
What were the results of IAEA-ACCtrial?<br></br>
“<span>5-yr LRC 42% 6 fx vs. 30% 5 fx<br></br>5-yr OS 35% vs. 28%, p=0.07<br></br>5-yr DSS 50% vs. 40%</span><br></br><br></br>More acute skin and mucositis in accel RT. No difference in late toxicity”
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
What was the patient population studied in DAHANCA 6 & 7?
“1485 glottic, supraglottic pharynx, oral cavity <span>not receiving chemo, treated with primary RT</span>”
<div>What was the regimen studied in DAHANCA 6 & 7?</div>
“→5 fx per week <br></br>vs. <br></br><span>→6 fx per week</span><br></br><br></br>66-68 Gy/ 33-34 fx, no chemo<br></br><span>Nimorazole</span> for all except for glottic”
What were the results of DAHANCA 6 & 7?
5-yr LRC 70% 6 fx vs. 60% 5 fx<br></br>14.5-yr LRF 22% vs. 29%<br></br>Larynx preservation 80% vs. 68%<br></br>5-yr DSS 73% vs. 66%<div><br></br>No change in OS<br></br>Acute morbidity more frequent with 6 fx</div>
<div>What trial investigated hyperfractionation with chemoRT?</div>
“DAHANCA 28,<span><a>Saksø et al, Radiother Oncol, 2020</a></span>”
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.<div><br></br></div><div><br></br></div>
<div>What was the patient population studied in DAHANCA 28 trial?</div>
50 HPV negative Stage III-IV H&N cancer
<div>What was the regimen studied in DAHANCA 28?</div>
Phase I/II<br></br><br></br>Hyperfx accel RT 76 Gy/ 56 fx BID with cisplatin + nimorazole<br></br><br></br>Primary endpoint: LRF
<div>What were the results of DAHANCA 28 trial?</div>
3-yr LRF 21%<br></br>3-yr OS 74%<br></br><br></br>acute severe dysphagia in 67%<br></br>acute severe mucositis in 61%<br></br><br></br>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
Conclusions from DAHANCA 28?
Hyperfx accel RT wih cisplatin and nimorazole is feasible. Although acute toxicity was high, late toxicity seems acceptable.
<div>What trial established PORT dosing as standard of care?</div>
“MDACC,<span><a>Ang et al, IJROBP, 2001</a></span>”
What is the clinical relevance of the study?
Low risk is unlikely to benefit from adjuvant RT.<div><br></br>Int risk benefits from mod dose adjuvant RT.</div><div><br></br>In high risk there is still opportunity for improvement in LRC.</div>
<div>What was the patient population studied in Ang 2001 IJROBP trial?</div>
“288<span>Post-op H&N</span><div><b><br></br></b>Low risk: 0 factors<br></br>Int risk: 1 factor, no ECE<br></br>High risk: ECE or >=2 factors<br></br><br></br>Factors: oral site, PNI, N+, ECE, +margin</div>”
<div>What was the regimen studied in Ang 2001 IJROBP?</div>
“<span>Low risk</span> - no PORT<br></br><span>Intermediate risk</span> - 57.6 Gy<br></br><span>High risk</span> - randomized:<br></br>→63 Gy/5 wks accel<br></br>vs. <br></br>→63 Gy/7 wks conv + 2 wks CCB”
<div>What were the results of Ang 2001 IJROBP</div>
<div>trial?</div>
Low Risk: 90% LRC, 83% OS<br></br>Int risk: 94% LRC, 66% OS<br></br>High Risk: 68% LRC, 42% OS <br></br><br></br>Trend to higher LRC when RT delivered in 5 vs. 7 weeks for high risk
Conclusions from Ang 2001 IJROBP?
Time <11 weeks gave better survival and LRC
What trials established addition of chemo to post-op RT for ENE/+margins as standard of care?
“EORTC 22931(<span><a>Bernier et al, NEJM, 2004</a>)</span><div><span><br></br></span></div><div>RTOG 9501 (<a>Cooper et al, NEJM, 2004</a>)</div>”
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
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
What was the regimen studied in EORTC 22931?
“→Post-op RT 66 Gy (54 Gy to low risk) vs. <br></br><span>same</span> <span>RT + cisplatin x3</span>”
What were the results of EORTC 22931 trial?
“5-yr PFS 36% vs. 47%<br></br><span>5-yr OS 40% vs. 53%</span><br></br>3-yr OS 49% vs. 65%<br></br>5-yr LRC 69% vs. 82%”
What was the patient population studied in RTOG 9501 trial?
459 pts operable H+N with ≥2 N+, ENE, or + margin
What was the regimen studied in RTOG 9501?
“→Post-op RT 60 Gy ± 6 Gy boost vs. <br></br><span>same RT + cisplatin x3</span>”
What were the results of RTOG 9501 trial?
“2-yr LRC 72% vs. 82%, p=0.01<br></br>5-yr LRC 11% vs. 13%<br></br>2-yr OS 57% vs. 63%, <b>p=0.19</b><br></br>5-yr OS 12% vs. 13%<br></br><br></br>For positive margins or ECE: <br></br>10-yr LRC 67% vs. 79%<br></br><span>10-yr OS 20% vs. 27%</span>”
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
What trials established addition of chemo to post-op RT as standard of care in certain cases?
<div>EORTC 22931(Bernier), RTOG 9501 (Cooper)</div>
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.
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.
<div>What was the patient population studied in EORTC 22931?</div>
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
<div>What trial established concurrent chemoradiation as standard of care?</div>
MACH-NC
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.
<div>What was the patient population studied in MACH-NC trial?</div>
17,346 pts H&N SCC trials comparing local treatment with chemo or without
<div>What were the results of MACH-NC?</div>
“Chemo (all forms of sequencing) had an <span>absolute 5-yr OS benefit of +4.5%. If concurrent chemo, 5-yr OS benefit is +8%.</span>”
<div>What trial established addition of cetuximab to RT in non-cisplatin patients?</div>
“University Alabama Birmingham,<span><a>Bonner et al, NEJM, 2006</a></span>”
What is the clinical relevance of the Bonner trial?
Adding cetuximab to RT improves LC and OS.<br></br>
<div>What was the patient population studied in Bonner trial?</div>
414 pts Stage III or IV nonmetastatic SCC of oropharynx, hypopharynx, or larynx
<div>What was the regimen studied in Bonner trial?</div>
→RT with concurrent cetuximab <br></br>vs. <br></br>→RT alone<br></br><br></br>RT conventional 70 Gy, or hyperfrac 72-76.8 Gy/ 1.2 BID, or CCB 72 Gy/ 42 fx
<div>What were the results of Bonner trial?</div>
Median LC 24 vs. 15 mos<br></br>2-yr LC 50% vs 41%<br></br>median OS 49 vs. 29 mos<div><br></br>3-yr OS 55% vs 45%. Acneiform rash and infusion reactions more common, but otherwise not more toxic.</div><div><br></br>OS for grade 2-4 acneiform rash 69 mos vs 25 without<br></br><br></br></div>
What trial analyzed addition of chemotherapy to hyperfractionated RT?
“<span><a>Brizel et al, NEJM, 1998</a></span>”
What is the clinical relevance of Brizel et al?
CRT with split course improves outcomes over hyperfrac RT without chemo.
<div>What was the patient population studied in Brizel trial?</div>
116 pt T3-4 cancers or T2N0 BOT
<div>What was the regimen studied in Brizel et al?</div>
→75 Gy hyperfx, 1.2 Gy BID<br></br>vs. <br></br>→concurrent RT cis/5FU (split 1 wk RT break at 40 Gy) → adj cis/5FU
<div>What were the results of Brizel trial?</div>
CRT improved 3-yr LC from 44% to 70%<br></br>RFS 61 vs. 41%. p=0.08<br></br>3-yr OS 34% vs. 55%, p=0.07<br></br>adverse effects similar
<div>What trial established evaluated concurrent chemo versus split course?</div>
“INT,<span><a>Adelstein et al, JCO, 2003</a></span>”
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.
<div>What was the patient population studied in Adelstein et al trial?</div>
295 pts Unresectable oral cavity, oropharynx, larynx, or hypopharynx
<div>What was the regimen studied in Adelstein et al?</div>
→70 Gy alone<br></br>vs. <br></br>→70 Gy + concurrent cisplatin x 3 <br></br>vs. <br></br>→split-course 70 Gy + cis/5-FU
<div>What were the results of Aldestein et al trial?</div>
Continuous CRT improved 3-yr OS (37% vs. RT 23% vs. split-course plus chemo 27%) and DFS, but increased Gr 3-4 toxicity
<div>What trial suggested benefit of induction chemo ?</div>
“GSTTC Italian Study Group,<span><a>Ghi et al, Ann Oncol, 2017</a></span>”
What is the clinical relevance of GSTTC Italian Study Group?
“Induction chemo improves OS, PFS, LRC, and CR and maintains compliance with chemoRT. <span>On subanalysis the best effect was with concurrent cetuximab. <br></br><br></br>Given the history of other negative inducation trials, results should be interpreted with caution.</span>”
<div>What was the patient population studied in GSTTC Italian Study Group trial?</div>
414 pt locally advanced, Stage III-IV AJCC V, nonmetastatic SCC<br></br><br></br>unresectable or low suitability for surgery
<div>What was the regimen studied in GSTTC Italian Study Group?</div>
→induction TPF <br></br>vs. <br></br>→no induction<br></br><br></br><br></br>→conc cis/5FU <br></br>vs. <br></br>→conc cetuximab<br></br><br></br>2x2 randomization
<div>What were the results of GSTTC Italian Study Group trial?</div>
“<span>Induction chemo improved OS, PFS, LRC, and CR</span><br></br>Median OS induction 55 vs. 32 mos<br></br>3-yr OS 58% vs. 47%<br></br>CR 43% vs. 28% <br></br>median PFS 31 mos vs. 19 mos<br></br>DM ~15%, not different<br></br><br></br><span>-</span><span>On subanalysis, better effect with conc cetuximab</span><span> and non-OPX site, but underpowered</span><br></br>-More febrile neutropenia with induction<br></br><span>-ChemoRT breaks not different</span>”
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.<br></br><br></br>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.
<div>What trials showed negative results of induction chemotherapy?</div>
DeCIDE, PARADIGM, Madrid study
What is the clinical relevance of Paradigm/Decide/Madrid?
“<span>No benefit to induction chemotherapy. Toxicity is increased.</span>”
<div>What was the patient population studied in DeCIDE trial?</div>
285 pts N2 or N3 SCC of H&N
<div>What was the regimen studied in DeCIDE?</div>
→Induction TPF, RT + conc THF <br></br>vs. <br></br>→RT + conc THF <br></br><br></br>H=hydroxyurea. RT to 74-75 Gy hyperfx
<div>What were the results of DeCIDE trial?</div>
“-No benefit in 30-mos OS, RFS, or DMFS<br></br>-Mortality ~30% in both arms<br></br><span>-Serious adverse events more common in induction arm 47% vs. 28%<br></br></span>-In the induction group, 122/124 completed RT”
<div>What was the patient population studied in PARADIGM trial?</div>
145 unresectable, low surgical curability T3/T4, N2/3 (but not T1N2), or organ preservation<br></br>
<div>What was the regimen studied in PARADIGM?</div>
→Induction TP, RT + conc carbo or docetaxol<br></br>vs. <br></br>→RT + conc cis<br></br><br></br>If poor response to induction: 72 Gy RT in 6 weeks with docetaxel<br></br>If favorable response: 70 Gy RT in 7 weeks with carboplatin AUC 1.5
<div>What were the results of PARADIGM trial?</div>
“No benefit in OS or PFS<br></br>3-yr OS ~75% and 3-yr PFS ~68% <br></br><span>-Serious adverse events in 52 vs. 22 pts<br></br>-Grade 3-4 mucositis 47% vs. 16%</span><br></br>-More febrile neutropenia with induction<br></br>-RT breaks similar, 6 vs. 5 pts<br></br>-Terminated due to slow accrual”
<div>What was the patient population studied in Madrid trial?</div>
439 unresectable, Stage III-IV AJCC V, nonmetastatic SCC
<div>What was the regimen studied in Madrid trial?</div>
→Induction TPF, RT + conc cis<br></br>vs. <br></br>→induction PF, RT + conc cis<br></br>vs.<br></br>→RT + conc cis
<div>What were the results of Madrid trial?</div>
“<span>No change in PFS, TTF, or OS</span><br></br>Median PFS ~14 mos, TTF 8 mos, OS 27 mos<br></br><span>-More neutropenia, odynophagia, stomatitis with induction chemo</span><br></br><span>-With induction 113/155 completed RT compared to 118/128 in RT alone arm</span>”
<div>What trial established noninferiority of PET vs neck dissection?</div>
“PET-NECK,<span><a>Mehanna et al, NEJM, 2016</a></span>”
What is the clinical relevance of PET-NECK?
“<span>OS is noninferior with neck dissection guided by PET vs. planned dissection in all.</span>”
<div>What was the patient population studied in PET-NECK trial?</div>
564 N2 or N3 SCC of H&N
<div>What was the regimen studied in PET-NECK?</div>
“Noninferiority<br></br><br></br><span>→chemoRT then PET in 3 mos then neck dissection only if incomplete or equivocal response <br></br></span>vs.<br></br>→planned neck dissection”
<div>What were the results of PET-NECK trial?</div>
Surgical complications 42% vs. 38%<br></br>2-yr OS 84.9% vs. 81.5%<br></br><br></br>HR for death slightly favored PET and indicated noninferiority
<div>What trial evaluated ommision of RT to dissected N0 neck?</div>
“Washington University,<span><a>Contreras et al, JCO, 2019</a></span>”
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.
<div>What was the patient population studied in Contreas trial?</div>
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.
<div>What was the regimen studied in Contreas study?</div>
Phase II. Omits RT to dissected N0 neck<br></br><br></br>IMRT SIB to 66/54 Gy or 60/52 Gy. Chemo as indicated.
<div>What were the results of Contreras trial?</div>
“<span>Control of uninvolved dissected neck 97%<br></br></span><br></br>Those that failed also failed at primary<br></br>5-yr LC 84%, RC 93%, PFS 60%, OS 64%<br></br><br></br>Characteristics: <span>59% N2-3, 51% T3-4, 71% crossed midline</span>, 34% had chemo”
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.)
<div>What trial studied sensitivity of PET in cN0 neck?</div>
“ACRIN 6685,<span><a>Lowe et al, JCO, 2019</a></span>”
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.
<div>What was the patient population studied in ACRIN 6685 trial?</div>
268 neck sides, H&N cancer with at least one cN0 neck that was planned for dissection, PET
<div>What was the regimen studied in ACRIN 6685?</div>
“<span>Prospective<br></br>PET → negative cN0 neck → dissection of that neck and evaluation of node status</span>”
<div>What were the results of ACRIN 6685 trial?</div>
“<span>-PET in cN0 neck was true negative in 87% after dissection</span><br></br><span>-If max SUV <3.5 in neck, NPV was 94%, specific to each node level<br></br>-PET changed decisions in 22%</span>”
<div>What trial evaluated omiting RT to tonsil primary post op bed?</div>
“U Penn<span><a>Swisher-McClure et al, IJROBP, 2019</a></span>”
“What is the clinical relevance of the UPenn<span><a>Swisher-McClure et al, IJROBP, 2019</a>?</span>”
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.
<div>What was the patient population studied in UPenn trial?</div>
60 tonsil HPV+ SCC pT1-pT2 N1-3 s/p TORS
<div>What was the regimen studied in UPenn Study?</div>
Omit RT to resected tonsil post-op bed if no indications to treat primary, and RT to neck with indications to treat neck
<div>What were the results of UPenn trial?</div>
2-yr primary LC 98.3% (n=1 recurrence)<br></br>2-yr regional recurrence 1.7%<br></br>2-yr DM 3.3%<br></br><br></br>Mean RT dose to primary 39.6 Gy
<div>What trials established IMRT to avoid xerostomia as standard of care?</div>
GORTEC 2004-01, RTOG 0022, PARSPORT
What is the clinical relevance of GORTEC 2004-01, RTOG 0022, PARSPORT?
IMRT reduces xerostomia
<div>What was the patient population studied in GORTEC 2004-01 trial?</div>
188 locally advanced H&N SCC
<div>What was the regimen studied in GORTEC 2004-01?</div>
→70 Gy/ 35 fx 3DCRT<br></br>vs. <br></br>→75 Gy/ 35 fx IMRT<br></br><br></br>50 Gy then sequential boost in both arms<br></br><br></br>Concurrent cisplatin in both
<div>What were the results of GORTEC 2004-01 trial?</div>
1-yr grade ≥2 xerostomia 63% vs. 23%<br></br>3-yr grade ≥2 xerostomia 45% vs. 11%<br></br><br></br>LR and OS not different
<div>What was the patient population studied in RTOG 0022 trial?</div>
69 oropharynx T1-2, N0-1
<div>What was the regimen studied in RTOG 0022?</div>
“<span>IMRT SIB 66/60-54 in 30 fx</span>. No chemo”
<div>What were the results of RTOG 0022 trial?</div>
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%
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.
<div>What was the patient population studied in PARSPORT trial?</div>
47 pharynx SCC T1-T4, N0-N3
<div>What was the regimen studied in PARSPORT?</div>
“60 or 65 Gy/ 30 fx <span>parotid sparing IMRT <br></br></span>vs. <br></br>conventional RT”
<div>What were the results of PARSPORT trial?</div>
IMRT improved xerostomia<br></br>12-mo xerostomia 38% vs 75%<br></br>24-mo xerostomia grade ≥2 29% vs 83%<br></br>QOL scores
<div>What trial established Larynx preservation as standard of care?</div>
<div></div>
VALSG (VA Larynx Study Group)
What is the clinical relevance of the VA Larynx Study?
Larynx preservation feasible and maintains OS outcomes.<br></br><br></br>Long-term QOL is superior with preservation.
<div>What was the patient population studied in VA Larynx trial?</div>
332 Stage III-IV (not T1N1)
<div>What was the regimen studied in VA Larynx Study?</div>
“→total laryngectomy + post-op RT (50-70 Gy) <br></br>vs. <br></br><span>→induction 3 cycles PF → </span>70 Gy if CR or PR. If no response: surgery+post-op RT”
<div>What were the OS, LF, DM results of VA Larynx trial?</div>
“No difference in 2-yr OS. CRT had worse LF but improved DM<div><br></br>2-yr OS 68%, not different<br></br>LF 12% vs. 2%<br></br>RF 8% vs. 5% (NS)<br></br>DM 11% vs. 17%, p=0.04<div><span><br></br><br></br></span></div></div>”
What was the rate of larynx preservation in VA Larynx trial?
<br></br>2-yr larynx preservation 64%. <br></br><br></br>-Long term QOL is improved with chemoRT. Better freedom from pain, emotional well being, less depression
<div>What trial established Concurrent chemoRT as standard of care in Larynx?</div>
“RTOG 9111,<span><a>Forastierre et al, NEJM, 2003<br></br>Forastierre et al, JCO, 2013</a></span>”
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.
<div>What was the patient population studied in RTOG 9111 trial?</div>
“547 Stage III-IV glottic or supraglottic (<span>excluded extension through thyroid cartilage, large volume T4a, and >1 cm BOT involvment. Limited T4 was allowed</span>) who would otherwise had required total laryngectomy<br></br><br></br>69% of patients were supraglottic”
<div>What was the regimen studied in RTOG 9111?</div>
“<span>→RT with concurrent cis 5FU x3<br></br>vs.<br></br>→induction cis/5FU → RT (VA regimen)<br></br></span>vs. <br></br>→RT alone 70 Gy”
<div>What were the 2 yr results of RTOG 9111 trial?</div>
“2-yr <span>larynx sparing 88%</span> vs. 75 vs. 70% <br></br>2-yr <span>LRC 78%</span> vs. 61% vs. 56%<br></br>”
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.<br></br><br></br><br></br>10-yr larynx sparing 82% vs. 68% vs. 64%<br></br>10-yr LC 69% vs. 54% vs. 50%<br></br><br></br>Long term f/u: <br></br><span>Deaths not attributed to larynx cancer worse with concurrent:<br></br>31%</span> vs. 21% vs. 17% <br></br><br></br><span>Trend to better OS with induction (p=0.08 vs. concurrent)</span><span><br></br>10-yr OS 28% vs. 39% vs. 32% (NS)</span><br></br>10-yr DM 16% vs. 16% vs. 24%<br></br><3% with inability to swallow”
<div>What trial established larynx preservation in hypopharyngeal cancer as standard of care?</div>
“EORTC 24891,<span><a>Lefebvre et al, JNCI, 1996<br></br>Lefebvre et al, Ann Oncol, 2012</a></span>”
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.
<div>What was the patient population studied in EORTC 24891 trial?</div>
202 SCC of pyriform sinus or AE fold
<div>What was the regimen studied in EORTC 24891?</div>
“→surgery + post-op RT <br></br>vs. <br></br><span>→induction cis/5FU → RT</span> if CR <br></br>(surgery for PR)<br></br><br></br>[Similar to VA trial]”
<div>What were the results of EORTC 24891 trial?</div>
“LF trend to higher with RT. Trend to less DM with chemo<div><br></br>3-yr larynx preservation 42%, <br></br>5-yr larynx preservation 35%<br></br><span>5-yr OS 33%, not different<br></br>10-yr OS ~13.5%, not different</span><br></br>10-yr chemoRT survival with functional larynx 8.7%<br></br><br></br></div>”
<div>What trial(s) established TPF as induction chemo for larynx preservation as standard of care?</div>
“GORTEC 2000-01,<span><a>Pointreau et al, JNCI, 2009<br></br></a></span>”
What is the clinical relevance of GORTEC 2000-01?
TPF resulted in superior response rates compared to PF in larynx sparing in hypoharynx cancer.
<div>What was the patient population studied in GORTEC 2001-01 trial?</div>
220 larynx or hypopharynx T3-T4 primary sites or T2 not appropriate for partial laryngectomy, requiring total laryngectomy
<div>What was the regimen studied in GORTEC 2000-01?</div>
→Induction TPF x3<br></br>vs. <br></br>→Induction PF<br></br><br></br>→ RT 70 Gy for CR or PR. <br></br><br></br>If no response, total laryngectomy and RT 54-66 Gy
<div>What were the results of GORTEC 2000-01 trial?</div>
Increased laryngeal preservation in TPF arm<div><br></br>3-yr laryngeal preservation 70% vs 58%<br></br>10-yr larynx preservation 70% vs 47%<br></br>10-yr larynx dysfunction free survival 64% vs. 37%<br></br>Response rates 80% vs 59%<br></br><br></br>More grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia with TPF, and more stomatitis and thrombocytopenia with PF</div>
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).
<div>What trial compared RT vs surgery in early stage larynx?</div>
“Helsinki University Central Hospital, Finland,<span><a>Aaltonen et al, IJROBP, 2014</a></span>”
What is the clinical relevance of Aaltonen et al?
“<span>RT seems to provide superior voice outcomes compared to surgery for early stage larynx cancer.</span>”
<div>What was the patient population studied in Aaltonen et al trial?</div>
60 T1a larynx
<div>What was the regimen studied in Aaltonen et al?</div>
“<span>→66 Gy </span><br></br>vs. <br></br>→CO2 laser<br></br><br></br>blinded experts rated voice quality on GRBAS scale, patient self-assessed voice quality and ADL impact, and blinded videostrobe”
<div>What were the results of Aaltonen et al trial?</div>
“<span>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</span>”
<div>What trial established hypofractionation as standard of care in early larynx?</div>
“<span><a>Yamazaki et al, IJROBP, 2006</a></span>”
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.
<div>What was the patient population studied in Yamazaki et al trial?</div>
180 T1N0 glottic
<div>What was the regimen studied in Yamazaki et al?</div>
2 Gy vs. 2.25 Gy fractions: <br></br>Minimal tumors (≤2/3 vocal cord) 60Gy vs. 56.25Gy<br></br>Larger tumors 66Gy vs. 63Gy
<div>What were the results of Yamazaki et al trial?</div>
5-yr LC 77% vs. 92% for 2.25 Gy/fx<br></br>No difference in 5-yr CSS or toxicity
<div>What trial showed unilateral treatment of well lateralized early T stage oral cavity?</div>
“University of Queensland, Brisbane, Australia,<span><a>Liu et al, ASTRO, 2018</a></span>”
“What is the clinical relevance of<span><a>Liu et al</a>?</span>”
In well-lateralized early T stage oral cavity, unilateral treatment is associated with low risk of contralateral failures.
<div>What was the patient population studied in Liu et al trial?</div>
“176<span>well lateralized T1-2 N0-2b oral cavity</span> s/p surgery & unilateral neck dissection ± RT to primary ± RT to unilateral neck<br></br>Excluded bilateral neck treatment, ECE, +margin, chemo”
<div>What were the results of Lui et al?</div>
5-yr bilateral or contralateral neck failures in 4.3%<div><br></br>17% had RT, 68% T1, and 55% N0</div>
<div>What trial established neck dissection in oral cavity as standard of care?</div>
“Tata Memorial Centre, Mumbai,<span><a>D’Cruz et al, NEJM, 2015</a></span>”
“What is the clinical relevance of<span><a>D’Cruz et al, NEJM, 2015</a></span>?”
“<span>Elective neck dissection results in improved DFS and OS.</span>”
<div>What was the patient population studied in D' Cruz trial?</div>
596 T1-2N0 oral cavity SCC
<div>What was the regimen studied in D'Cruz?</div>
“Resection then<br></br><span>→ipsilateral neck dissection</span> <br></br>vs. <br></br>→obs (LND for recurrence)”
<div>What were the results of D'Cruz trial?</div>
OS 80% vs. 68%<br></br>DFS 70% vs. 46%<br></br>Some suggestion of benefit with DOI >3 mm, p=0.12
<div>What trial showed SLNB equivalent to neck dissection in early stage oral caivty?</div>
“Senti-MERORL,<span><a>Garrel et al, JCO, 2020</a></span>”
What is the clinical relevance of Senti-MERORL?
“<span>SLNB and neck dissection are equivalent in early stage SCC. SLNB is preferred.</span>”
<div>What was the patient population studied in Senti-MERORL trial?</div>
307 T1-2N0 oral cavity SCC
What was the regimen studied in Senti-MERORL?
“Equivalence:<br></br>Resection then<br></br><span>→ipsilateral neck dissection</span> <br></br>vs. <br></br>→SLNB and LND if positive”
<div>What were the results of Senti-MERORL trial?</div>
2-yr neck RFS 90% vs. 91% <br></br>(equivalent)
<div>What trial established concurrent chemoRT in orophaynx as standard of care?</div>
“University of Queensland, Brisbane, Australia,<span><a>Denis et al, IJROBP, 2003</a></span>”
“What is the clinical relevance of<span><a>Denis et al, IJROBP, 2003</a></span>?”
The addition of concurrent chemo improves LC and OS without increase in late toxicity in oropharynx.
“<div>What was the patient population studied in<span><a>Denis et al, IJROBP, 2003</a></span>trial?</div>”
226 Stage III/IV oropharynx
“<div>What was the regimen studied in<span><a>Denis et al, IJROBP, 2003</a></span>?</div>”
→70 Gy with carbo/5-FU x3 <br></br>vs. <br></br>→RT alone
“<div>What were the results of<span><a>Denis et al, IJROBP, 2003</a></span>trial?</div>”
“<span>CRT improved 5-yr LC 48% vs. 25%</span><br></br>5-yr DFS 27% vs. 15%<br></br>5-yr OS 22% vs. 16%, increased acute but not late toxicity”
<div>What trial compared conventional fractionation with chemo versus accleterated RT?</div>
“GORTEC 99-02,<span><a>Bourhis et al, Lancet, 2012</a></span>”
What is the clinical relevance of GORTEC 99-02?
“<span>Conventional fractionation with chemo results in superior OS and lower toxicity compared to accelerated RT.</span>”
<div>What was the patient population studied in GORTEC 99-02trial?</div>
559 Stage III or IV SCC
<div>What was the regimen studied in GORTEC 99-02?</div>
1) RT 70 Gy/7 weeks with carbo/5FU<div><br></br>2) Acc RT 70 Gy/6 weeks (2 Gy daily for 40 Gy then 1.5 BID) with carbo/5FU/</div><div><br></br>3) Very Acc RT 64.8 Gy/3.5 weeks, no chemo</div>
<div>What were the results of GORTEC 99-02trial?</div>
“<span>Slight improvements with conventional RT</span><br></br><span>3-yr OS 43% Conv</span> vs. 39% vs. 37%<br></br>3-yr LFR 42% vs. 45% vs. 50%<br></br>3-yr DM 25% vs. 34% vs. 28% (NS)<br></br>G3-4 mucosal toxicity 69% vs. 76% vs. 84%<br></br>Feeding tube 60% vs. 64% vs. 70%,”
<div>What trial established risk stratification of HPV+ oropharynx?</div>
“RTOG 0129<span><a>Ang et al, NEJM, 2010<br></br></a></span>”
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.<div><br></br></div><div>Also established HPV risk stratification</div>
<div>What was the patient population studied in RTOG 0129 trial?</div>
323 Stage III-IV SCC or oral cavity, oropharynx, hypopharyx, or larynx
<div>What was the regimen studied in RTOG 0129?</div>
→Standard RT 70 Gy with cisplatin<br></br>vs. <br></br>→accelerated fractionation with concominant boost (AFX-CB) 72 Gy in 6 weeks concurrent cis
<div>What were the results of RTOG 0129trial?</div>
“3-yr OS HPV+/HPV-: 82% vs. 57%<br></br>3-yr DM HPV+/HPV-: 9% vs. 15%<br></br><span>3-yr LRC HPV+/HPV-: 86% vs. 65%</span><br></br><br></br>For RT regimens, No difference in 8-yr OS, PFS, LRF, DM, or toxicity”
What was the 3yr OS in different risk gorups in RTOG 0129?
3-yr OS by RPA group (see commentary for classes):<br></br>Low risk: 93%<br></br>Int risk: 71%<br></br>High risk: 46%<br></br><br></br><br></br>
<div>What trial evaluated TORS versus RT in early oropharynx?</div>
<div></div>
“ORATOR,<span><a>Nichols et al, Lancet, 2019</a></span>”
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.<br></br>
<div>What was the patient population studied in ORATOR trial?</div>
“68 Oropharynx T1-2, N0-1 or N2b (up to two nodes ≤3cm) HPV+/-<br></br><br></br><span>88% were HPV+</span>”
<div>What was the regimen studied in ORATOR?</div>
Phase II<br></br>TORS and neck dissection [71% had post-op RT] vs. RT with or without chemotherapy
<div>What were the results of ORATOR trial?</div>
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).
<div>What trial compared concurrent cisplatin versus cisplatin +cetuximab?</div>
<div></div>
RTOG 0522
What is the clinical relevance of RTOG 0522?
Adding cetuximab to RT and cisplatin did not improve outcomes.
<div>What was the patient population studied in RTOG 0522 trial?</div>
891 oropharynx Stage III or IV
<div>What was the regimen studied in RTOG 0522?</div>
concurrent cisplatin+cetuximab vs. cisplatin<br></br>AccCB/IMRT
<div>What were the results of RTOG 0522 trial?</div>
No diff in 3 yr OS (76% vs. 73%) or PFS (59% vs. 61%). With cetuximab, mucositis and skin reactions worse.
<div>What study evaluated ipsilateral neck radiation in tonsil?</div>
“Princess Margaret Hospital,<span><a>O’Sullivan et al, IJROBP, 2001<br></br>Huang et al, IJROBP, 2017</a></span>”
What is the clinical relevance of the O’Sullivan study?
Ispilateral neck radiation in tonsil cancer T1-T2N1-N2b results in excellent control.<br></br><br></br>There is no difference per HPV status.
<div>What was the patient population studied in Princess Margaret Hospital study?</div>
228 Ipsilateral tonsil, no surgery
<div>What was the regimen studied in Princess Margaret Hospital study?</div>
Retrospective. RT only to ipsilateral side, no chemo
<div>What were the results of Princess Margaret Hospital study?</div>
“-Contralateral failure: T1 0%, T2 1.5%, T3 10%, T4 0%, N0 0%, N1 9%, N2/3 0%.<div><br></br><span>-Sig risk for failure if involving medial one third of palate, BOT</span></div><div><span><br></br></span>-No difference in LC or RC for HPV+ vs. HPV- in 379 patients from 1999-2014</div>”
<div>What trials evaluated Cetuximab vs. Cisplatin in HPV + oropharynx?</div>
“RTOG 1016<span><a>Gillison et al, Lancet, 2019</a></span><div><br></br></div><div>De-Escalate,<a>Mehanna et al, ESMO, 2018</a><br></br></div>”
What is the clinical relevance of RTOG 1016?
“<span>Cetuximab with RT resulted in inferior OS and PFS compared to cisplatin in HPV+ oropharynx. Toxicity is not reduced with cetuximab.</span>”
<div>What was the patient population studied in RTOG 1016trial?</div>
849 HPV+ locally advanced oropharynx p16+. T1-2 N2a-3 or T3-4, and N
<div>What was the regimen studied in RTOG 1016?</div>
“→RT 70 Gy in 6 weeks (DAHANCA) SIB 56 & 52.5 Gy with concurrent<br></br><span>cisplatin</span> <br></br>vs. <br></br>→cetuximab”
<div>What were the results of RTOG 1016?</div>
“<span>5-yr OS 85%</span> vs. 78%<br></br>5-yr PFS 78% vs. 67%<br></br><span>5-yr LRF 10%</span> vs. 17%<br></br><span>5-yr DM 9% </span>vs. 12%<br></br>Severe and acute toxicity similar”
What is the clinical relevance of the De-Escalate study?
“<span>Cetuximab with RT resulted in inferior OS and LC compared to cisplatin in HPV+ oropharynx. Toxicity is not reduced with cetuximab.</span>”
<div>What was the patient population studied in De-Escalatetrial?</div>
304 Stage III-IV (T3N0, T4N0, T1N1-T2N3) HPV+ oropharynx cancer. Excludes N2b, N2c, >10 PY
<div>What was the regimen studied in De-Escalate?</div>
→70 Gy in 6 weeks with<br></br>cisplatin <br></br>vs. <br></br>→cetuximab
<div>What were the results of De-Escalatetrial?</div>
2-yr OS 98% vs. 89%<br></br>2-yr any recurrence 16% vs. 6%<br></br>Severe and any grade toxicity similar
<div>What trial evaluated chemoRT versus RT alone in Oropharynx HPV+ T1-2, N1-2b, or T3,N0-2b and <10 PY?</div>
“NRG HN002,<span><a>Yom et al, ASTRO, 2019</a></span>”
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.
<div>What was the patient population studied in NRG HN002trial?</div>
296 Oropharynx HPV+ T1-2, N1-2b, or T3,N0-2b and <10 PY
<div>What was the regimen studied in NRG HN002?</div>
Phase II<br></br>→60 Gy IMRT with weekly cis<br></br>vs. <br></br>→60 Gy alone<br></br><br></br>Endpoint: PFS >85%
<div>What were the results of NRG HN002trial?</div>
IMRT+cis: 2-yr PFS 91%, p=0.035 <br></br>IMRT: 2-yr PFS 88%, p=0.088%, CI extends below 85%<br></br>Dsyphagia scores acceptable in both arms
What isNRG HN005 studying?
“Oropharynx HPV+ T1-3, N1, and <10 PY (AJCC 8)<div>→70 Gy in 6 weeks (DAHANCA) + cisplatin<br></br>vs.<br></br>→60 Gy/ 30 fx + cisplatin<br></br>vs.<br></br>→60 Gy/ 30 fx + nivolumab<span><br></br></span></div>”
<div>What trial studied HPV+ post-op intermediate risk RT dose?</div>
“EGOC 3311,<span><a>Ferris et al, ASCO, 2020</a></span>”
What is the clinical relevance of the ECOG 3311?
“All approaches led to favorable outcomes in HPV+ oropharynx.<br></br><br></br>TORS and adjuvant 50 Gy RT for intermediate risk warrants comparison to chemoRT in a phase III trial.<div><br></br></div><div>Phase II<br></br>TORS →<br></br><span>• Low risk (negative margins, no ECE, 0-1 nodes): <br></br></span>-observed <span><br></br>• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):</span> <br></br>-50 Gy vs. 60 Gy<br></br><span>• High risk (>1 mm ENE, positive margins, or ≥5 nodes)</span>: <br></br>-66 Gy RT weekly cisplatin</div>”
<div>What was the patient population studied in ECOG 3311 trial?</div>
377 Resectable oropharynx cancer stage III-IV, p16+, who undergo TORS
<div>What was the regimen studied in ECOG 3311?</div>
“Phase II<br></br>TORS →<br></br><span>• Low risk (negative margins, no ECE, 0-1 nodes): <br></br></span>-observed <span><br></br>• Intermediate risk (close margins, <5 nodes, ENE ≤1 mm):</span> <br></br>-50 Gy vs. 60 Gy<br></br><span>• High risk (>1 mm ENE, positive margins, or ≥5 nodes)</span>: <br></br>-66 Gy RT weekly cisplatin”
<div>What were the results of ECOG 3311 trial?</div>
2-yr PFS<br></br>Low risk: 94%<br></br>Int risk (50 Gy vs. 60 Gy): 95% vs. 96%<br></br>High risk: 91%
What is PATHOS trial studying?
“Oropharynx cancer stage II-III (T1-T3, N0-2b, <10 PY), p16+, who undergo TORS<div><br></br></div><div>Intermediate risk: 50 Gy IMRT vs. 60 Gy<br></br>High risk: 60 Gy IMRT vs. 60 Gy with weekly cisplatin<span><br></br></span></div>”
What isEORTC 1420-HNCG-ROG studying?
“Oropharynx Stage I/II HPV+/-<div><br></br></div><div>TORS and neck dissection <br></br>vs. RT<span><br></br></span></div>”
What is ORATOR2 studying?
“<span>T1-2, N0-2, p16 +/-</span><div><span>TORS and neck dissection <br></br>vs. <br></br>RT with or without chemotherapy</span><span><br></br></span></div>”
What trial suggests benefit of sequencing of chemotherapy?
“<span><a>Zhang et al, JAMA Netw Open, 2019</a></span>”
“What is the clinical relevance of<span><a>Zhang et al,</a>?</span>”
Induction chemo and concurrent chemo should be recommended in nasopharynx cancer. Adjuvant chemo should be avoided.
<div>What was the patient population studied in Zhang el al trial?</div>
8036 Nasopharynx
<div>What was the regimen studied in Zhang el al?</div>
Meta-analysis of 28 randomized trials to evaluate benefit of neoadjuvant, concurrent, and adjuvant chemo<br></br><br></br>Trial sequence approach and fixed or random effects model
<div>What were the results of Zhang el al trial?</div>
Induction chemo improves OS, PFS, DM, and LRC<br></br><br></br>Concurrent chemo improves OS, PFS, DM, and LRC<br></br><br></br>Adjuvant chemo did not improve outcomes
<div>What trial suggests benefit of chemo in nasopharynx?</div>
“MAC-NPC<span><a>Petit et al, ASCO, 2020</a></span>”
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.
<div>What was the patient population studied in MAC-NPC trial?</div>
8221 Nasopharynx <br></br>All subtypes
<div>What was the regimen studied in MAC-NPC?</div>
Meta-analysis of 28 trials<br></br><br></br>2 outlier trials were excluded
<div>What were the results of MAC-NPCtrial?</div>
Induction with taxane gave best OS when evaluating individual types of chemo<br></br><br></br>When combining all types of chemo, adjuvant chemo had better OS than induction
<div>What trial established concurrent and adjuvant chemo as standard of care?</div>
<div></div>
“INT 0099<span><a>Al-Sarraf et al, JCO, 1998<br></br>Al-Sarraf et al, Pro Am Soc Clin Oncol 2001</a></span>”
What is the clinical relevance of INT 0099?
Concurrent and adjuvant chemo added to RT results in OS benefit in nasopharynx.
<div>What was the patient population studied in INT 0099trial?</div>
193 Stage III-IV (would include some current T2)
<div>What was the regimen studied in INT 0099?</div>
“→70 Gy <br></br>vs. <br></br><span>→70 Gy + concurrent cisplatin x3 & adj cisplatin 5FU x3</span>”
<div>What were the results of INT 0099trial?</div>
“<span>3-yr OS 78% vs. 47%</span>. PFS 69% vs. 24%<br></br>5-yr OS 67% vs 37%, PFS 58% vs 29%”
<div>What study evaluated chemo sequencing?</div>
“Hong Kong,<span><a>Lee et al, Cancer, 2020</a></span>”
“What is the clinical relevance of<span><a>Lee et al, Cancer, 2020</a>?</span>”
Induction chemotherapy with PX may improve PFS and OS compared to adjuvant chemotherapy with conventionally fractionated RT.
“<div>What was the patient population studied in<span><a>Lee et al, Cancer, 2020</a></span>trial?</div>”
803 nasopharynx Stage III-IVB, nonkeratinizing
“<div>What was the regimen studied in<span><a>Lee et al, Cancer, 2020</a></span>?</div>”
6 arms: <br></br>1) adj PF, conventional RT<br></br>2) ind PF, conventional RT<br></br>3) ind PX, conventional RT<br></br>4) adj PF, 6 fx weekly RT<br></br>5) ind PF, 6 fx weekly RT<br></br>6) ind PX, 6 fx weekly RT
“<div>What were the results of<span><a>Lee et al, Cancer, 2020</a></span>trial?</div>”
No difference with RT regimens<br></br>Overall, no difference in induction/adj <br></br><br></br>On exploratory analysis, some difference with induction/adj with conventional RT only:<br></br>5-yr PFS 78% vs. 62%<br></br>5-yr OS 84% vs. 72%<br></br>better PFS with PX over PF induction<br></br>5-yr PFS 78% vs. 62%
<div>What trials established concurrent chemoRT in nasopharynx as standard of care?</div>
Taichung Veterans Hospital, Taiwan<div><br></br></div><div>Sun Yat-sen University, Guangzhou, China<br></br></div>
What is the clinical relevance of the Taichung Veterans Hospital, Taiwan study?
Concurrent chemo added to RT results in improved OS.
<div>What was the patient population studied in Taichung Veterans Hospital, Taiwantrial?</div>
284 Stage III-IV M0<br></br>WHO grade I-III
<div>What was the regimen studied in Taichung Veterans Hospital, Taiwan?</div>
→70-74 Gy <br></br>vs. <br></br>→70-74 Gy with concurrent cisplatin 5FU
<div>What were the results of Taichung Veterans Hospital, Taiwantrial?</div>
5-yr OS 54% vs 72%<br></br>5-yr PFS 53% vs 72%
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.
<div>What was the patient population studied in Sun Yat-sen University, Guangzhou, Chinatrial?</div>
230 T1-2N1 or T2N0 with parapharyngeal involvement, WHO grade II-III
<div>What was the regimen studied in Sun Yat-sen University, Guangzhou, China?</div>
→68-70 Gy alone <br></br>vs. <br></br>→68-70 Gy with weekly cisplatin
<div>What were the results of Sun Yat-sen University, Guangzhou, China trial?</div>
Chemo RT improved OS, PFS, DMFS, LRC:<br></br>5-yr OS 86% vs 95%<br></br>5-yr LRC 91% vs 93%<br></br>5-yr PFS 78% vs 88%<br></br>5-yr DMFS 84% vs 95%
<div>What trial showed no benefit to adjuvant chemo in nonkeritinizing nasopharynx?</div>
“Sun Yat-sen University, Guangzhou, China,<span><a>Chen et al, Lancet Oncol, 2012</a></span>”
“What is the clinical relevance of the<span><a>Chen et al, Lancet Oncol, 2012</a></span>study?”
There is no benefit to adjuvant chemotherapy.
“<div>What was the patient population studied in<span><a>Chen et al, Lancet Oncol, 2012</a></span>trial?</div>”
251 Stage III/IV (not T3 or T4)<br></br>nonkeratinizing
“<div>What was the regimen studied in<span><a>Chen et al, Lancet Oncol, 2012</a></span>?</div>”
RT to ≥66 Gy in 2.0-2.27 Gy / fx with concurrent weekly cisplatin →<br></br><br></br>adjuvant cisplatin 5FU x3 <br></br>vs. no adjuvant
“<div>What were the results of<span><a>Chen et al, Lancet Oncol, 2012</a></span>trial?</div>”
2-yr FFS 86% vs 84%, p=0.13<br></br>2-yr OS 94% vs 92%, p=0.32<br></br>2-yr DMS 88% vs 86%, p=0.12<br></br>2-yr LRFFS 98% vs 95%, p=0.10
<div>What studies showed benefit of induction chemo in nasopharynx?</div>
“Sun Yat-sen University, Guangzhou, China<span><a>Sun et al, Lancet Oncol, 2016</a></span><div><br></br></div><div>Sun Yat-sen University, Guangzhou, China<a>Zhang et al, NEJM, 2019</a><br></br></div>”
“What is the clinical relevance of the<span><a>Sun et al, Lancet Oncol, 2016</a></span>study?”
Addition of induction TPF to chemoRT improved FFS. Longer term follow-up is needed.
“<div>What was the patient population studied in<span><a>Sun et al, Lancet Oncol, 2016</a></span>trial?</div>”
241 Stage III-IVB <br></br>nonkeratinizing
“<div>What was the regimen studied in<span><a>Sun et al, Lancet Oncol, 2016</a></span>?</div>”
→Induction TPF then RT with cisplatin <br></br>vs. <br></br>→chemoRT alone
“<div>What were the results of<span><a>Sun et al, Lancet Oncol, 2016</a></span>trial?</div>”
3-yr FFS 80% vs 72%<br></br>Grade 3-4 neutropenia 42% vs 7%<br></br>Grade 3-4 leucopenia 41% vs 17%<br></br>Grade 3-4 stomatitis 41% vs 35%
“What is the clinical relevance of the<span><a>Zhang et al, NEJM, 2019</a></span>study?”
Induction chemo added to chemoRT improves RFS and OS compared to no induction chemo.
“<div>What was the patient population studied in<span><a>Zhang et al, NEJM, 2019</a></span>trial?</div>”
480 Stage IIIB-IVB<br></br>nonkeratinizing
“<div>What was the regimen studied in<span><a>Zhang et al, NEJM, 2019</a></span>?</div>”
gem/cis induction vs. no induction prior to chemoRT<br></br><br></br>RT to 66-70 Gy/ 30-33 fx with concurrent cisplatin
“<div>What were the results of<span><a>Zhang et al, NEJM, 2019</a></span>trial?</div>”
3-yr RFS 85% vs. 77%<br></br>3-yr OS 95% vs. 90%<br></br>acute grade 3-4 toxicity 76% vs. 56%<br></br>late grade 3-4 toxicity 9% vs. 11%
<div>What trial showed no benefit of induction for nasopharynx?</div>
“National Cancer Centre Singapore, Singapore<span><a>Tan et al, IJROBP, 2015</a></span>”
“What is the clinical relevance of the<span><a>Tan et al, IJROBP, 2015</a></span>?”
There is no benefit to induction chemotherapy in nasopharynx cancer.
“<div>What was the patient population studied in<span><a>Tan et al, IJROBP, 2015</a></span>trial?</div>”
172 Nasopharynx <br></br>WHO II-III
“<div>What was the regimen studied in<span><a>Tan et al, IJROBP, 2015</a></span>?</div>”
→RT with concurrent weekly cisplatin <br></br>vs. <br></br>→induction gem/carbo/paclitaxel x2 with chemoRT
“What were the results of <span><a>Tan et al, IJROBP, 2015</a></span>?<br></br>”
No difference in 3-yr OS, 92% GCP vs 94%. <br></br>No difference in DFS or DMFS<br></br>After GCP, more dose de-intensification of cis were required
<div>What trial established treated of primary of nasopharynx in metastatic setting as standard of care?</div>
“Sun Yat-sen University<span><a>You et al, JAMA Oncol, 2020</a></span>”
“What is the clinical relevance of <span><a>You et al, JAMA Oncol, 2020</a></span>?”
Locoregional treatment in metastatic nasopharynx cancer improves OS and reduces DM.
“<div>What was the patient population studied in<span><a>You et al, JAMA Oncol, 2020</a></span>trial?</div>”
126 Metastatic nasopharynx cancer with CR or PR after PF x3<br></br><br></br>(only 1.5% were keratininzing)
“<div>What was the regimen studied in<span><a>You et al, JAMA Oncol, 2020</a></span>?</div>”
PF x3, then if CR or PR→<br></br><br></br>→PF x6 then 70 Gy IMRT to primary<br></br>vs. <br></br>→PF x6 <br></br><br></br>Primary endpoint: OS
“<div>What were the results of<span><a>You et al, JAMA Oncol, 2020</a></span>trial?</div>”
2-yr OS 76% C+RT vs. 55% chemo<br></br>2-yr DM 54% vs 68%<br></br>2-yr PFS 35% vs. 4%<br></br><br></br>About 70% had ≥3 metastases
What isNRG-HN001 studying?
“<span>Stage II-IVB with detectable EBV DNA</span><div><span><br></br></span></div><div><span>RT with concurrent cisplatin, then test EBV DNA. Then<br></br>if detectable EBV, then consolidation 5-FU/cisplatin x3 vs gem/paclitaxel x4<br></br>if undetectable EBV, then consolidation 5-FU/cisplatin x3 vs obs</span><span><br></br></span></div>”
<div>What trial established IMRT of nasopharynx as standard of care?</div>
<div></div>
RTOG 0225
What is the clinical relevance of RTOG 0225?
“<span>Outcomes with this IMRT SIB regimen are improved over Intergroup 0099.</span>”
<div>What was the patient population studied in RTOG 0225 trial?</div>
68 Nasopharynx Stage I-IVB
<div>What was the regimen studied in RTOG 0225?</div>
“<span>IMRT to 70 Gy/59.4 Gy in 33 fx</span>. For ≥T2b or N+: concurrent cisplatin and adjuvant cis/5FU”
<div>What were the results of RTOG 0225trial?</div>
“<span>2 yr LC 92%, 2 yr OS 80%</span>, 2-yr regional PFS 91%, 2-yr DMF 86%<br></br>acute grade 4 mucositis 4%, late grade 3 dysphagia 5%, xerostomia 3%, long term PEG 4%”
<div>What study evaluated ChemoRT versus observation following salvage surgery after recurrence?</div>
“GETTEC/GORTEC<span><a>Janot et al, JCO, 2008</a></span><br></br>”
“What is the clinical relevance of the<span><a>Janot et al, JCO, 2008</a></span>study?”
“<span>Salvage chemoRT improves DFS but not OS compared to no treatment. Toxicity can be significant.</span>”
“<div>What was the patient population studied in<span><a>Janot et al, JCO, 2008</a></span>?</div>”
130 Recurrent or 2nd primary H&N cancer in a previously irradiated area
“<div>What was the regimen studied in<span><a>Janot et al, JCO, 2008</a></span>?</div>”
Salvage surgery then: <br></br>→Obs <br></br>vs. <br></br>→60 Gy in 11 weeks with concurrent 5FU and hydroxyurea
“<div>What were the results of<span><a>Janot et al, JCO, 2008</a></span>?</div>”
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.
<div>What trial established fesability of chemoRT in recurrence of HN?</div>
“RTOG 9610<span><a>Spencer et al, Head Neck, 2008</a></span>”
What is the clinical relevance of RTOG 9610?
ChemoRT for recurrent H&N cancer is feasible with acceptable adverse effects.
<div>What was the patient population studied in RTOG 9610?</div>
“86 Recurrent SCC or ““second primary”” in prev irradiated field, unresectable. RT finished >6 mos prior”
<div>What was the regimen studied in RTOG 9610?</div>
Phase II. RT to 60 Gy in 1.5 Gy BID per fx<br></br>3DCRT allowed. Chemo with 5FU/hydroxyurea.
<div>What were the results of RTOG 9610trial?</div>
2 yr-OS 15%, 5-yr OS 5%. Better survivial if >1 year interval from recurrence. F/u 16 months<br></br><br></br>Acute grade 4 in 18%, grade 5 in 8%. Late grade 3-4 toxicity 9%
<div>What study looked at reirradiation of recurrent HN?</div>
“MIRI Collaborative<span><a>Caudell et al, IJROBP, 2017</a></span>”
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.
<div>What was the patient population studied in MIRI Collaborative?</div>
505 Recurrent H&N undergoing reirradiation with IMRT
<div>What were the results of MIRI Collaborative?</div>
Elective neck RT and hyperfx did not improve LRF or OS.<br></br>≥66 Gy improved OS and LRF.<div><br></br>Dose did not obviously affect outcomes in post-op reirradiation.</div><div><br></br>Highest rates of late toxicity in hyperfx and post-op RT.</div>
