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Head and Neck CancersSession Chair: Sue S. Yom, MD PhD

Department of Radiation Oncology University of California San Francisco

Assistant to Session Chair• Christopher H. Chapman, MD MS – UCSF, Radiation Oncology Resident

Panel Members

• Alain Algazi, MD UCSF, Medical Oncology

• Beth Beadle, MD PhD Stanford, Radiation Oncology

• A. Dimitrios Colevas, MD Stanford, Medical Oncology

• Patrick Ha, MD UCSF, Head and Neck Oncologic Surgery

• Chris Holsinger, MD Stanford, Head and Neck Oncologic Surgery

• Jed Katzel, MD Kaiser Permanente, Medical Oncology

• Shyam Rao, MD PhD UC Davis, Radiation Oncology

• Jonathan Reiss, MD MS UC Davis, Medical Oncology

Case 1

45 year-old man, persistent sore throatRemote 10 pack-year smoking history, otherwise healthy

Physical Exam:• Right tonsillar fossa mass• 2 palpable ipsilateral nodes, not fixed/matted

Tonsil biopsy p16+ oropharynx SCC

Imaging: • 2 cm primary tumor, 0.5 cm soft palate extension• No base of tongue or posterior pharyngeal wall extension• 2 cystic lymph nodes in ipsilateral level II, max 2.8 cm• No radiographic evidence of extranodal extension• No distant disease by PET

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STAGINGAJCC 7th Ed. AJCC 8th Ed.

cT1 N2b M0 stage IVA cT1 N1 M0 stage I

AJCC 8th ed. Clinical nodal stage: p16+ oropharynx

• cN1: Ipsilateral node(s), all ≤ 6 cm

• cN2: Bilateral/contralateral node(s), all ≤ 6 cm

• cN3: Any node > 6 cm

STAGINGAJCC 7th Ed. AJCC 8th Ed.

cT1 N2b M0 stage IVA cT1 N1 M0 stage I

cN0 cN1 cN2 cN3

cT0 I II III

cT1 I I II III

cT2 I I II III

cT3 II II II III

cT4 III III III III

Clinical Stage Grouping: p16+ oropharynx

8th Ed.

cN0 cN1 cN2 cN3

cT0 III IVA IVB

cT1 I III IVA IVB

cT2 II III IVA IVB

cT3 III III IVA IVB

cT4a IVA IVA IVA IVB

7th Ed.

Question 1.1This patient is not interested in surgical options.Treatment recommendation?1. Radiation with concurrent cisplatin2. Radiation with concurrent cetuximab3. Induction chemotherapy then carboplatin-RT4. Induction chemotherapy then cetuximab-RT5. Radiation alone

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RTOG 10-16: Phase III Trial of Radiotherapy Plus Cetuximab versus Chemoradiotherapy

in HPV-Associated OPSCC

OPSCC p16+ IHCAll M0 stages

p16 central reviewStratification by T/N stage, KPS, Smoking

Accelerated IMRT70 Gy in 6 weeks

Cisplatin 100 mg/m2 x 2c

Accelerated IMRT70 Gy in 7 weeks

Cetuximab 8 doses

RANDOMIZE

Paradigm

ParadigmStage III/IV SCCHN

• Oral cavity, oropharynx, hypopharynx, larynx

• Expected N=330

RANDOMIZE

DocetaxelCisplatin

5-FUevery 3 weeks, 3 cycles Docetaxel (every week for 4 wks)

Daily/twice-daily RT (days 1-5)6 weeks

Carboplatin (every week)Daily RT (days 1-5)

7 weeks

Cisplatin (weeks 1, 4)Daily/twice-daily RT (days 1-5)

6 weeks

CR

PR

ICT CRT

DeCIDE

DeCIDEChemotherapy and RT-

naïve SCCHN• Expected N=400

RANDOMIZE

Docetaxel (day 1)Cisplatin (day 1)5-FU (days 1-5)

every 3 weeks, 2 cycles Docetaxel (day 1)5-FU (days 0-4)

Hydroxyurea (days 0-4)Twice-daily RT (days 1-5)every 2 weeks, 5 cycles

ICT CRT

Two randomized phase III studies of induction + chemoRT vs chemoRT

in U.S. :ParadigmDeCIDE

E1308: Phase II Trial of Induction Chemotherapy Followed Reduced-Dose Radiation and Weekly Cetuximab in Patients

with HPV-associated Resectable OPSCCMarur et al., J Clin Oncol 2016

All reduced dose patients (n=51) ≤ 10 pk-yr and < T4N2c (n=27)

2-yr PFS 80% 2-yr OS 94% 2-yr PFS 95% 2-yr OS 95%

80 patients with HPV/p16+ stage III-IV OPSCCIC cisplatin/paclitaxel/cetuximab x3c

70% CR 54 Gy / 27 frx with concurrent cetuximab30% < CR 69.3 Gy / 33 frx with concurrent cetuximab

All patients: 2-yr PFS 78%, 2-yr OS 91%

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NRG HN-002: A Randomized Phase II Trial for Patients with p16 Positive, Non-smoking Associated,

Locoregionally Advanced Oropharyngeal Cancer

OPSCC p16+ IHC≤ 10 pk-yr smoking hx

T1-2, N1-2bor T3, N0-2b

p16 central reviewStratification by unilateral vs. bilateral RT

60 Gy in 6 weeksCisplatin 40 mg/m2 weekly

60 Gy in 5 weeks(no chemotherapy)

RANDOMIZE

44% of RTOG 10-16 population eligible. Closed to accrual.

Patient changes his mind, now wants surgery:

Transoral surgical resection (TORS)with ipsilateral selective neck dissection

Final Pathology: 2.5 cm tumor, no PNI/LVI

4/25 +LN, largest 3 cm with 1 mm extra-nodal extensionClear margins (> 5 mm)

STAGINGAJCC 7th Ed. AJCC 8th Ed.

pT2 N2b M0 stage IVA pT2 N1 M0 stage I

AJCC 8th ed. Pathological nodal stage: p16+ oropharynx

• pN1: 4 or fewer involved nodes

• pN2: More than 4 involved nodes

• pN3: … no pN3 for p16+

Number of Positive Nodes is Superior to Lymph Node Ratio and AJCC N Staging for Prognosis of Surgically Treated HNSCCRoberts et al., Cancer 2016

SEER analysis12,437 patients treated 2004-2012

Ove

rall

Surv

ival

Ove

rall

Surv

ival

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STAGINGAJCC 7th Ed. AJCC 8th Ed.

pT2N2bM0 stage IVA pT2N1M0 stage I

pN0 pN1 pN2

pT0 I II

pT1 I I II

pT2 I I II

pT3 II II III

pT4 II II III

Clinical Stage Grouping: p16+ oropharynx

8th Ed.

pN0 pN1 pN2 pN3

pT0 III IVA IVB

pT1 I III IVA IVB

pT2 II III IVA IVB

pT3 III III IVA IVB

pT4a IVA IVA IVA IVB

7th Ed.

Question 1.2• 2.5 cm tumor, no PNI/LVI• 4/25 +LN, largest 3 cm with 1 mm extra-nodal extension• Clear margins (> 5 mm)What adjuvant therapy would be recommended?1. Concurrent chemoradiation with CDDP 100 mg/m2 Q3 wks2. Standard radiation therapy alone (60-66 Gy)3. Dose de-escalated radiation alone (50 Gy)4. None/observation

EORTC 22931 / RTOG 9501 Combined AnalysisBernier et al., Head Neck 2005

ECOG 3311: Phase II Randomized Trial of TORS Followed by Low-Dose or Standard-Dose IMRT in Resectable p16+ Locally Advanced OPSCC

p16+ OPSCC

cT1-3, N1-2b(No T1N1)

TORS + Neck Dissection

Low Risk:pT1-2N0-1

Margin ≥ 3 mm

Intermediate:Margin < 3mm≤ 1 mm ECE

pN2a-bPNILVI

High Risk:Pos. Margins> 1 mm ENE≥ 5 +LN

RANDOMIZE

Observation

IMRT 50 Gy / 25 Fx

IMRT 60 Gy / 30 Fx

IMRT 66 Gy / 33 FxCDDP 40 mg/m2 Qwk

Unknown:pN2c or N3

E3311 INV v.08/15/16ecog-acrin.org

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• The patient receives adjuvant cisplatin chemoradiation• 6 months follow-up: new back pains• PET-CT: 2 liver metastases, no bony metastasis• MRI Brain: no evidence of intracranial metastases• KPS 80%

Question 1.3Systemic therapy choice?1. Docetaxel2. Cisplatin/5FU/Cetuximab3. Nivolumab4. Pembrolizumab

EXTREMEN = 442

Untreated recurrent or metastatic squamous-cell carcinoma of the head and neck

220 pts: cisplatin 100 mg/m2 or carboplatin AUC 5 mg/ml-min, plus fluorouracil 1000 mg/m2 x 4 days x 6 cycles

222 pts: same chemotherapy plus cetuximab 400 mg/m2 loading then 250 mg/m2 weekly until disease progression

Vermorken et al, N Engl J Med 2008; 359:1116-1127

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and NeckR. L. Ferris et al., NEJM, Nov. 2016

• 361 patients• Progression within 6 months of

platinum chemotherapy

• No brain metastases

• Randomized to:

– nivolumab (3 mg/kg Q2wks)– other single agent therapy

(MTX, docetaxel, cetuximab)

• 1 year OS 36% vs. 16.6%

• Grade 3-4 toxicity: 13% vs. 35%

• Greater effect if PD-L1 ≥ 1% (non-significant)

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PembrolizumabKEYNOTE-012

T.Y. Seiwert et al., Lancet Oncol 2016

• N=60, recurrent/metastatic• All express PD-L1 > 1%• 38% HPV+, 85% tobacco hx• 70% had 2+ previous tx• Pembrolizumab monotherapy• ORR 18%

• 25% in HPV-positive• 14% in HPV-negative

KEYNOTE-055J. Bauml et al., ASCO 2016

• N=50 (prelim of 172)• All progressed on Pt/cetuximab• Median f/u 6.8 months• 84% had 2+ previous tx• Pembrolizumab monotherapy• ORR 18%

• 22% in HPV-positive• 16% in HPV-negative• 17% in PD-L1 > 1%• 8% in PD-L1 ≤ 1%

Case 230 year-old woman, hearing loss and trismusPhysical Exam:• Middle ear effusion, pain with jaw opening• No cranial nerve deficits• Bilateral cervical lymphadenopathy • Nasopharygoscopy: friable mass at fossa of Rosenmüller

Biopsy Undifferentiated carcinoma, EBV+

Imaging: • 3 cm right lateral nasopharygeal wall mass• Parapharyngeal extension and medial pterygoid muscle involvement• Bilateral cervical lymphadenopathy in levels II and III up to 3 cm

STAGINGAJCC 7th Ed. AJCC 8th Ed.

cT4 N2 M0 stage IVA cT2 N2 M0 stage III

T2:• Parapharyngeal extension• Medial and lateral pterygoids

T4: • Further soft tissue extension • Parotid gland• Intracranial, cranial nerves, orbit,

hypopharynx (unchanged)

(N3a + N3b) N3: node > 6 cm or supraclavicular fossa (defined as below cricoid)

J.J. Pan et al. Cancer, 2015

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STAGINGAJCC 7th Ed. AJCC 8th Ed.

cT4 N2 M0 stage IVA cT2 N2 M0 stage III

N0 N1 N2 N3

T0 II III IVA

T1 I II III IVA

T2 II II III IVA

T3 III III III IVA

T4 IVA IVA IVA IVA

AJCC Stage Grouping: Nasopharynx

N0 N1 N2 N3

T0 II III IVB

T1 I II III IVB

T2 II II III IVB

T3 III III III IVB

T4 IVA IVA IVA IVB

7th ed. 8th ed.

Question 2.1Treatment recommendation?1. Radiation with concurrent cisplatin2. Cisplatin-RT followed by cisplatin/5FU3. Induction cisplatin/5FU then cisplatin-RT4. Induction docetaxel/cisplatin/5FU then cisplatin-RT5. Radiation therapy alone

Y. Sun et al., Lancet Oncol 2016

480 patients, stage III-IVB (except T3-4N0)

All receive RT (median 70 Gy) + cisplatin (100 mg/m2 Q3 weeks)Randomized to ± 3 cycles induction TPF:docetaxel 60 mg/m2, CDDP 60 mg/m2, 5FU 600 mg/m2 x 5 days

3-year OS: 86 92% p = 0.029

3-year DFFS: 83 90% p = 0.031

Ribassin-Majed et al., JCO 2016

5,144 patients in 20 trials91% stage III-IVBMedian follow-up 7.4 years

HR for mortality (OS) vs. RT aloneCRT: 0.77, 5-yr ARR 8%CRT-AC: 0.65, 5-yr ARR 12%IC-CRT: 0.81, 5-yr AB 6% (non-sig)

HR for distant failure vs. RT aloneCRT: 0.68, 5-yr AB 8%CRT-AC: 0.59, 5yr AB 11%IC-CRT: 0.44, 5yr AB 15%

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Question 2.2The patient receives concurrent cisplatin-RTWould you recommend plasma EBV DNA level testing?1. No2. Yes, before RT3. Yes, after RT4. Yes, before and after RT5. Yes, at recurrence

J-C Lin et al., New Engl J Med 2004

99 patients: neoadjuvant cisplatin/5FU then 70-74 Gy RT

Pre-treatment: 94/99 patients with detectable plasma EBV DNA Post-treatment: 10/99 patients with detectable plasma EBV DNA

Question 2.3She has a clinical complete response to therapy, but post-treatment plasma EBV DNA levels are detectable.Further treatment options?1. Observation only2. Cisplatin/5FU3. Gemcitabine/Paclitaxel4. Other

NRG HN-001: Randomized Phase II and Phase III Studies of Individualized Treatment for NPC

Based on Biomarker EBV DNAStage II-IVB NPC

Detectable pre-treatment plasma EBV DNA

IMRT 70 Gy / 33 FractionsCisplatin 40 mg/m2/week

Gemcitabine/Paclitaxel x 4c

RANDOMIZE RANDOMIZE

Control:Cisplatin/5FU x 3c

Observation

Post-CRT EBV DNA Detectable Post-CRT EBV DNA Undetectable

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She receives adjuvant cisplatin/5FU.12 months after treatment:• Enlarged low left supraclavicular node• FDG-PET+ SCV and mediastinal LNs, LLL lung nodule• Plasma EBV DNA levels highly elevated

Question 2.4Chemotherapy choice for metastatic disease?1. Cisplatin/5FU2. Cisplatin/gemcitabine3. Gemcitabine/carboplatin then adoptive T-cell transfer4. Pembrolizumab

L. Zhang et al., Lancet Oncology, 2016

362 patients: 54% prior platinum, 27% prior 5FURandomized to cisplatin/5FU or gemcitabine/cisplatin Q 3 weeks, up to 6xMedian follow-up 19.4 months

12-month PFS:20% Gem/Cis vs. 6% Cis/5FUp < 0.0001

Median OS:29.1 mo Gem/Cis vs.20.9 mo Cis/5FUp = 0.0025

35 patients, first-line for metastatic diseaseOverall response rate 71.4%. 2-year overall survival 63%, 3-year OS 37%LMP2-specificity correlated with overall survival

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KEYNOTE-028C. Hsu et al., ESMO Asia 2015

Phase Ib27 patients with NPC, must express PD-L1 ≥ 1%Pembrolizumab 10 mg/kg Q2 weeks 2 years or progressionOverall response rate (monotx) 26%

Case 375 year-old man with history of numerous actinic keratoses• Presents with 2 cm left antihelix nodule:• No immunosuppression• No prior resections at this site• No palpable lymphadenopathy

Biopsy: Well-to-moderately diff. SCC

Mohs resection:• 2.9 cm final deficit• Negative margins after 2 stages• 6 mm maximum thickness• Twig of perineural invasion

STAGINGAJCC 7th Ed. AJCC 8th Ed.

pT2NxMx pT3NxMx

AJCC 8th ed. cutaneous carcinomas:

Stage T3:• >= 4 cm maximum dimension• Minor bone erosion• Perineural invasion (nerve > 0.1 mm)• Depth > 6 mm or beyond subcutaneous fat

(Does not apply to melanoma or Merkel cell carcinoma)

Question 3.1Adjuvant therapy recommendations?1. None, observation only2. Radiation to primary site3. Radiation to primary site and ipsilateral neck

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K.D. Brantsch et al., Lancet Oncology, 2008

Multivariate analysis of 615 patients with cutaneous SCC treated with surgery alone

Best predictors of locoregional recurrence:Desmoplastic growth (HR 16)Thickness > 6.0 mm (HR 6)

Best predictors of metastatic disease:Thickness > 6.0 mm (HR 4.8)Immunosuppression (HR 4.3)

Tumor site = Ear (HR 3.6)Tumor width > 5 cm (HR 2.2)

Desmoplasia or > 6.0 mm3-yr LRRFS: 99% vs. 86%

> 6.0 mm vs. < 2.0 mm3-yr DMFS: 100% vs. 88%

No adjuvant therapy surveillance with q3 months H&P

9 months later, palpable left parotid noduleUS-guided FNA of 1.5 cm intraparotid LN: SCC

Superficial parotidectomy and ipsilateral selective neck dissection• 2/23 nodes involved with metastatic SCC

– 1 intraparotid node (1.5 cm)– 1 level II cervical node (1.0 cm)– No ENE

MRI and PET-CT: no other metastatic disease

Question 3.2Adjuvant therapy recommendations?1. Radiation therapy alone2. Radiation with concurrent carboplatin3. Radiation with concurrent cetuximab

Post-Operative Skin Trial (POST)TROG 05.01

Post-op concurrent CRT versus RT

High-risk post-op H&N SCC

Any of:• T3-4 (no nose/EAC/lip)• pN2b-3 cervical LN• ENE• Intraparotid LN• In-transit metastases

RANDOMIZE

Radiotherapy Alone60-66 Gy in 2 Gy/frx

Radiotherapy + Carboplatin60-66 Gy in 2 Gy/frxCarboplatin AUC 2.0

Primary endpoint: Locoregional failure

Closed to enrollment with 321 patients, currently maturing

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He receives adjuvant RT alone (60 Gy in 30 frx).

18 months later, worsening hip and back pain.

Imaging shows multiple bony metastases to pelvis and spine.

Question 3.3Chemotherapy choice for metastatic disease?1. Paclitaxel2. Carboplatin doublet3. Cetuximab4. Pembrolizumab

ImmunotherapyCase reports for cutaneous SCC

A.L.S. Chang et al., JAMA Dermatol, 2016D.C. Tran et al., JAMA Dermatol, 2016

10 months

6 patients with unresectable/metastatic SCC, all immunocompetentAll previously received carboplatin, paclitaxel, and/or cetuximab5 received pembrolizumab, 1 nivolumab, Q 3 weeks1 patient CR, 4 patients PR (figure), 1 patient progressive diseaseProgression free survival: median 5.5 months, range 3 to 21 months

Case 4

60 year-old man with hoarseness, fixed neck mass50+ pack-year smoking history, quit at presentation

Laryngoscopy:Right supraglottic massInvolving false cord, piriform sinusRight arytenoid fixed, TVC not seenLeft TVC: normal mobility

Biopsy:Moderately-diff. SCCNo PNINo LVI

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STAGINGAJCC 7th Ed. AJCC 8th Ed.

cT3N2bM0 stage IVA cT3N3bM0 stage IVB

AJCC 8th Ed. Nodal Staging:For all primaries other than p16+ OPC and EBV+ NPC

Clinical Extra-Nodal Extension (ENE) cN3bMust be definite ENE to count

Any pathological ENE Increase pN stage by +1ENEmi is ≤ 2 mmENEma is > 2 mm

Question 4.1Recap: T3 larynx cancer with indeterminate cartilage invasionand ipsilateral multiple nodes with extra-nodal extensionTreatment recommendations?1. Surgery followed by chemoradiation2. Cisplatin + radiation3. Cetuximab + radiation4. Induction chemotherapy followed by radiation5. Induction chemotherapy followed by platinum-radiation6. Induction chemotherapy followed by cetuximab-radiation

J. Bonner et al., 2016

From original 424 patients, subset of 168 with larynx or hypopharynx cancer90 received cetuximab-RT, 78 received RT alone (dose/fractionation MD’s choice)

3-year OS: 42% vs. 39% (NS)

3-year LFS: 37% vs. 29% (p = 0.17)

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213 patients with stage III-IV laryngeal carcinomaRandomized to induction PF vs. TPFAll received RT (70 Gy) ± concurrent chemo by institution (15-20% received)

Overall response rate to induction: 80% vs. 59% (p = 0.002)

No sig. difference in 10-year OS (23-30%), LRC (21-28%), or DFS (19-25%)

GORTEC 2000-01: Long-Term Results of a Multicenter Randomized Phase III Trial of Induction Chemotherapy With Cisplatin, 5-fluorouracil, ± Docetaxel for Larynx Preservation

G. Janoray et al., J Natl Cancer Inst, 2016

10-year LP: 70% vs. 47% (p = 0.01) 10-year LDFFS: 64% vs. 37% (p = 0.001)

TPF Induction RT+Cetuximab

TREMPLINLefebvre et al., JCO 2013

Spanish HNCG: TTCC-2007/02Mesía et al., IJROBP 2016

• Randomized phase II• Stage II – IVA (89% III – IVA)• 56 patients (cetuximab arm)

• Induction TPF: 85% response• 2-year LDFS = 72%• 3-year OS = 71%

• 40-50% grade 3-4 toxicity

• No significant differences from TPF RT+cisplatin arm

• Single arm phase II• Stage III - IVA• 93 patients

• Induction TPF: 82% response• 2-year LDFS = 72%• 3-year OS = 78%

• 47% grade 3-4 toxicity

Question 4.2For which advanced-stage laryngeal cancer patients do you offer larynx-preserving approach (chemo-RT)?1. Stage T3 and lower only2. T1-3 and select T4 patients3. Based on adequate laryngeal function regardless of stage4. Based on induction chemotherapy response regardless of

stage

Question 4.2This patient (7th ed. cT3N2b) receives concurrent cisplatin-RT.At 4 weeks, complete clinical response in primary/nodes.Additional post-therapy disease status evaluation?1. PET-CT at 4-6 weeks2. PET-CT at 6-8 weeks3. PET-CT at 10-12 weeks4. PET-CT at 20-24 weeks

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PET-NECK Trial: PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer

H. Mehanna et al., N Engl J Med, 2016

564 HNSCC patients with N2a-3 disease (79% N2a-b)Randomized to planned neck dissection or PET-CT at 12 weeks post-CRT