Head and Neck Cancersmulticancers.org/previouscourses/2017/documents/slides/...Induction...
Transcript of Head and Neck Cancersmulticancers.org/previouscourses/2017/documents/slides/...Induction...
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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