Head And Neck Squamous Cell Carcinoma

Multimodality treatment of head and neck SCC R5 林育靖 / P 洪瑞隆

Outline

Introduction, staging

Who needs multimodality treatment

Incorporate chemotherapy to definitive local tx

Adjuvant

Induction

Concurrent

Organ preservation

Laryngeal cancer as an example

Head and neck cancer

Heterogeneous disease

Oral cavity, oropharynx, larynx, hypopharynx

Mostly SCC

Common etiology: smoking and drinking (betel nut for oral ca)

Similar biological behavior

Today’s topic

Nasopharynx:

WHO class type III: undifferentiate ca (NPC)

Nasal and paranasal sinus

Salivary gland

Anatomy

Generally, T stage

Depends on anatomical location, complicate

General concept of T stage

T1, T2: confined, not invade adjacent tissue

T3: larger, may invade adjacent tissue

T4: deeply invade adjacent tissue/organ

4a, 4b: depends on extend of invasion

Critical structure: skull base, pre-veterbral fascia, internal carotid artery, mediastinum

T stage of oropharyngeal cancer T1 T2 T3 T4a T4b Invade to adjacent tissue, less extensive Invade to adjacent tissue, more extensive

Ipsilateral Contralateral N1 Single,< 3 cm Single ipsilateral, < 3cm

N2a Single ipsilateral, 3-6cm Contralateral Ipsilateral Single, 3-6 cm

N2b Multiple ipsilateral, < 6cm Ipsilateral < 6 cm Contralateral

N2c Bilateral or contralateral, < 6cm Ipsilateral < 6 cm Contralateral

N3 Any LN > 6cm Ipsilateral > 6 cm Contralateral

Staging M0 N3 Any T M1 Any N Any T Stage IVc M0 Any N T4b Stage IVb M0 N2 T4a M0 N2 T3 M0 N2 T2 M0 N2 T1 M0 N1 T4a M0 N0 T4a Stage IVa M0 N1 T3 M0 N1 T2 M0 N1 T1 M0 N0 T3 Stage III M0 N0 T2 Stage II M0 N0 T1 Stage I

Resectability

Depends on T stage

T1, T2: resectable

T3: may be resectable

T4: mostly unresectable

Depends on surgical team

Wide excision  reconstruction

ENT surgeon  plastic surgeon

Depends on patients

Organ preservation

Definitive local therapy

Historically

Resectable: surgery +/- RT

Primary tumor: margin positive or close, perineural invasion, vascular embolism

LN: multiple, extracapsular extension

Unresectable: RT alone

Incorporate chemotherapy into local therapy

PF in 1 st line: RR 70-90%, CR 15-30%

Incorporation of chemotherapy

Before definitive treatment:

Induction/neoadjuvant chemotherapy

After definitive treatment

Adjuvant/consolidation chemotherapy

Concurrent with radiotherapy

Concurrent chemoradiotherapy

Intergroup 0034 Laramore GE et al. Int J Radiat Oncol Biol Phys 1992; 23: 705-713 442 pts, resectable, III/IV, SCC C/T x 3 Surgery XRT XRT Cisplatin 100mg/m2, D1 5-FU 1000mg/m2/d IVF 24hrs, D1-D5 q3w Compliance of adjuvant C/T: 63% Surgery 30% Larynx 17% Hypopharynx 26% 27% Oropharynx Oral NS 38% 46% DFS NS 44% 46% OS 0.03 NS p 23% 15% Dist Mets 24% RT 19% CT/RT LRR 4 yrs

NCI 443 pts, resectable, III/IV, SCC C/T x 1 XRT XRT Surgery C/T x 6 XRT Surgery C/T x 1 Surgery Cisplatin 100mg/m2, D1 Bleomycin 15mg/m2, D3-D7 Cisplatin 80mg/m2, monthly Compliance: 9% complete 6 cycles 27% complete > 3 cycles 45% received none A B C Cancer 1987; 60: 301-311 J Clin Oncol 1990; 8: 838-847 19% Larynx 35% Hypopharynx 46% Oral NS 45% 37% 35% OS NS 64% 49% 55% DFS 22% 42% B 0.011 (C vs A) NS p 13% 24% Dist Mets 30% C 41% A LRR 5 yrs

Adjuvant chemotherapy

Poor drug delivery

Decrease distant metastasis

No effect on locoregional control

No survival impact

Owing to insufficient dose density?

Disease nature-related?

British Journal of Cancer 2000; 83: 1594-1598 GETTEC, French 318, HNSCC, oropharynx stage II-IV Induction C/T Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 3 cycles Operable: Surgery  RT Inoperable: RT Operable: Surgery  RT Inoperable: RT

chemotherapy No chemotherapy Overall survival p=0.03 chemotherapy No chemotherapy Dz-free survival p=0.11 GETTEC, French

Journal of the National Cancer Institute 1994; 86: 265-272 Journal of the National Cancer Institute 2004; 96: 1714-1717 GSTTC, Italy 237, HNSCC, stage III/IV Induction C/T Operable: Surgery  RT Inoperable: RT Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 4 cycles Operable: Surgery  RT Inoperable: RT A B Oral cavity Para-nasal sinus Hypopharynx Oropharynx 73% 71% Inoperable 29% A 27% Operable B

All pts Operable group Inoperable group Overall survival Overall survival Overall survival 3-yr distant metastasis rate 0.01 31% 3% Operable 0.04 p value 42% B 24% A Inoperable

SWOG 158, Head Neck epidermoid carcinoma, stage III/IV Induction C/T Surgery  RT Cisplatin 50mg/m2, D1 MTX 40mg/m2, D1 Bleomycin 15U/m2, D1, D8 Vincristine 2mg, D1 Q3w, 3 cycles A B Laryngoscope 1988; 98: 1205 Surgery  RT  No survival benefit 21% 16% 28% 35% Oral cavity Larynx Hypopharynx Oropharynx 0.07 28% 49% Distant mets 48% 40% Local recur 23% 31% DFS p 38% 40% OS 24% B 14% A Regional recur 4yr

Induction chemotherapy

Good drug delivery

GSTTC, SWOG

No improvement of locoregional control

No survival impact

GSTTC: negative impact in surgery group

859 pts, HNSCC stage III/IV HFxRT Conventional RT Sanchiz F et al. Int J Radiat Oncol Biol Phys. 1990; 19: 1347-1350 CCRT (conventional RT) 60Gy/30fx, 2Gy/d 70.4Gy, 1.1Gy bid 5FU 250mg/m2, qod <0.01(A v B) <0.01(A v C) <0.01(A v B) <0.01(A v C) p 96.3% 90% 67.8% RR 37% 31% 17% 10yr DFS 42% C: CCRT 40% B: HFxRT 17% A: RT 10yr OS 36% Larynx 10% Other 14% Hypopharynx 11% Nasopharynx 29% Oral cavity

Journal of Clinical Oncology 1994; 12: 2648-2653 175 pts, HNSCC T3/T4 RT alone CCRT Identical RT in both arms RT: 60Gy/30fx, conventional C/T: 5-FU 1200mg/m2/d, infusion D1-D3, D22-D24 More mucositis, weight loss, and skin toxicity in CCRT arm Browman GP et al 0.04 56% 68% Complete response 0.08 42% 58% 3yr OS 0.057 p value 30% RT 40% CCRT 3yr PFS 27% Larynx 5% Other 14% Hypopharynx 42% Oropharynx 12% Oral cavity

100 pts, HNSCC stage III/IV RT alone CCRT RT: 66-72Gy, conventional, 1.8-2Gy/fx Aldelstein DJ et al Cancer 2000; 88: 876-883 Cisplatin: 20mg/m2/d 5FU: 1000mg/m2/d Infusion, D1-D4 D22-D25 Primary site resection +/- neck dissection Residual dz or recurrence Survival benefit from better local control <0.001 77% 45% Local control without resection 0.004 42% 34% OS with primary site preserve 75% 51% 48% RT 0.55 50% OS 0.09 84% Dist. Mets-free survival 0.04 p value 62% CCRT RFS 5yr 36% Larynx 16% Hypopharynx 44% Oropharynx 4% Oral cavity

Journal of National Cancer Institute 1999; 91:2081-2086 GORTEC 226 pts, oropharynx III/IV RT alone CCRT Identical RT in both arms RT: 7000cGy/35fx, conventional Dose delivery q3w, 3 cycles Carbo 70mg/m2/d, D1-D4 5FU 600mg/m2/d, D1-D4 0.02 42% 66% LR control 0.04 20% 31% DFS NS 11% 11% Dist. mets 0.02 p value 42% RT 51% CCRT OS 3yr 6960 cGy CCRT 6920 cGy RT dose RT 67% 66% 3rd 88% 86% 2nd 1st 98% 5FU 98% Carbo

Journal of Clinical Oncology 2000; 18: 1458-1464 130 pts, HNSCC stage III/IV HFxRT alone CCRT (HFxRT) Identical RT in both arms RT: 77Gy/70fx/35d, 1.1Gy bid C/T: 5FU 6mg/m2/d, 5days/wk Similar stomatitis, esophagitis in both arm, more leukopenia and thrombocytopenia in CCRT arm Jeremic B et al, Japan 0.0013 57% 86% Dist. Mets-PFS 0.0075 25% 46% OS 0.041 36% 50% Local recur.-PFS 0.0068 p value 25% RT 41% CCRT PFS 5yr 17% Larynx 9% Nasophaynx 16% Hypopharynx 37% Oropharynx 21% Oral cavity

Journal of Clinical Oncology 2003; 21: 92-98 ECOG RTOG 295 pts, HNSCC unresectable III/IV A: RT alone B: CCRT surgery Cisplatin 100mg/m2, D1, D22, D43 C: CCRT (RT 3000cGy) CR or unresectable CCRT (RT 4000cGy) PR CCRT (RT 3000cGy) Cisplatin 75mg/m2, D1 5FU 1000mg/m2/d x 4d q4w x 3 RT: 7000cGy/35fx, conventional identical in three arms 9% Larynx 19% Hypopharynx 59% Oropharynx 13% Oral cavity 0.001(A vs C) 0.05(B vs C) 73% 85.1% 92.6% Treatment compliance NS 0.014 (A vs B) p 27% 37% 23% 3y OS 19.1% 21.8% 17.9% Dist. Mets as first site C B A

Journal of Clinical Oncology 1994; 12: 385-395 215 pts, HNSCC stage III/IV, unresectable RT 70Gy/35fx C/T  RT (A) CCRT (B) Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 Q3w x 3 Cisplatin 60mg/m2, D1 5-FU 800mg/m2, D1-D5 Qw x 7 Taylor SG et al NS p=0.011 11% Larynx 27% Hypopharynx 6% Nasopharynx 23% Oropharynx 32% Oral 1% Sinus 55% 41% 3-yr dz specific survival 42% 36% 3-yr OS 7% 10% Dist Mets 41% 55% LR recurrence B A 81% 79% 88% B No difference % RT delay 78% % RT(>65Gy) 97% % 5-FU 97% % Cisplatin A

Enhance locoregional control

Minimal effect in distant metastasis

Improve survival

Superior than sequential chemoradiotherapy

Disease nature: local recurrence predominant

Enhance RT toxicity

Mucositis, skin toxicity, BW loss

Leukopenia depends on C/T type

J Clin Oncol. 1995; 13: 876-83 Annals of Oncology 2004; 15: 1179-1186 Brockstein B et al Induction C/T x 3 CCRT Intensified CCRT 164 pts 230 pts Cisplatin 100mg/m2, D1 5FU 640mg/m2/d, CVI, D1-D5 Leucovorin 100mg q4h po, D1-D6 INF- α 2MU/m2/d, D1-D6 q3w PFLI 5FU 800mg/m2/d x 5/wk Hydroxyurea 1000mg q12h, 11doses/wk RT 6000cGy/30fx FHX 5FU 800mg/m2/d x 5/wk Hydroxyurea 1000mg q12h, 11doses/wk RT 6000cGy/30fx Cisplatin 100mg/m2, D1 or Paclitaxel 100mg/m2, D1 q3w x 3 + PFLI-FHX (C/T)HF2X

Distant failure Locoregional failure Overall survival Progression-free survival J Clin Oncol. 1995; 13: 876-83 Annals of Oncology 2004; 15: 1179-1186

C/T impact on failure pattern

Induction or adjuvant chemotherapy

Related to systemic dose, adequate delivery?

Chemotherapy concurrent with RT

Decrease locoregional recurrence

Enhance RT effect

Add induction chemotherapy to CCRT

To reduce distant failure since local control adequate

42 pts, HN cancer, stage III/IV resectable/unresectable C/T x 2 CCRT Non-responder operation Cisplatin 20mg/m2/d x 4d 5FU 800mg/m2/d x 4d LV 500mg/m2/d x 4d q4w C/T: CCRT: RT: 70Gy/35fx Cisplatin 100mg/m2, q3w Yale 6557 protocol

Induction C/T: RR 76%

C/T  CCRT: 67% CR

Journal of Clinical Oncology 2004; 22: 3061-3069 79% 2yr Distant control 76.3% 2y Local control 52.4% 5y OS 54% 5y PFS 9% Unknown 9.5% NPC 7.5% 19% 38% 24% Hypopharynx Tonsil Tongue base Larynx

59 pts, HN cancer, resectable stage III/IV C/T x 2 CCRT Cisplatin 100mg/m2 5FU 1000mg/m2/d x 5d q3w C/T: CCRT: RT: 72Gy/36fx Cisplatin 100mg/m2, q3w SWOG Non-responder Non-responder operation operation

Journal of Clinical Oncology 2005; 23: 88-95 37 pts 22 pts Hypopharynx Tongue base 52% 3y PFS with Organ preservation 64% 3y OS 57% 3y PFS

Incorporate Taxane

Improve response rate in metastatic dz

70%  90%

Incorporate to induction regimen

Eliminate more micrometastasis

Journal of Clinical Oncology 2002; 20: 3964-3971 53 pts, HNSCC, oropharynx, stage III/IV C/T x 2 CCRT Carboplatin AUC 6 Paclitaxel 200mg/m2 q3w Non-responder Surgery  RT C/T x 2 Neck dissection N2/N3 dz University of Pennsylvania RT: 70Gy/35fx/7wk Paclitaxel 30mg/m2/wk CCRT: Historical control: similar pts, OP  RT, 3-yr dist.mets: 30% Am J Otolaryngol 2001; 22:329-335 Induction C/T: RR 89% C/T  CCRT: 90% CR 77% Organ preserve 19% Distant metastasis 17% Locoregional recurrence 70% OS 59% 3-yr EFS

Journal of Clinical Oncology 2003; 21: 320-326 University of Chicago 9502 protocol 69 pts, HN cancer, stage III/IV C/T x 2 CCRT Carboplatin AUC 2, D1,8,15 Paclitaxel 135mg/m2, D1 q3w C/T: CCRT: RT: 75Gy, 1.5Gy bid, D1-D5 Paclitaxel 100mg/m2, D1 5FU 600mg/m2/d, D1-D5 Hydroxyurea 500mg q12h x 11 N2/N3 Neck dissection Residual disease operation Historical control: same CCRT regimen without induction C/T Journal of Clinical Oncology 2001; 19: 1961-1969

9% Unknown 4% Nasopharynx 1% Submaxill gl. 33% 10% 44% 9% Oral cavity Larynx Hypopharynx Oropharynx 19% 13% 60% 63% Historical control 8% Distant metastasis 7% Locoregional recurrence 70% OS 80% 3yr PFS

Journal of Clinical Oncology 2004; 22: 4905(abstr 5508)

Journal of Clinical Oncology 2005; 23: 8636-8645 382 pts, HNSCC stage III/IV CF x 3 PCF x 3 Hitt R et al, Spain Paclitaxel 175mg/m2, D1 Cisplatin 100mg/m2, D2 5FU 500mg/m2/d, D2-D6 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d, D1-D5 q3w q3w CCRT Cisplatin 100mg/m2, q3w RT 7000cGy/35fx CR or PR>80% Poor responder Salvage surgery 30% Larynx 23% Hypopharynx 34% Oropharynx 13% Oral cavity 65% Unresectable 35% Resectable

Hitt R et al, Spain Journal of Clinical Oncology 2005; 23: 8636-8645 0.03 26m 36m Time to tx failure 0.03 37m 43m Median survival Induction <0.001 14% 33% CR <0.001 16% 53% mucositis p value 36% CF 37% PCF neutropenia Dose density <0.001 81% 91% Cisplatin 99% Paclitaxel <0.001 p value 91% CF 98% PCF 5FU

Ongoing trials HNSCC, locally advanced Induction C/T CCRT CCRT Journal of Clinical Oncology 2006; 24: 2624-2628

Induction chemotherapy

Phase II seemed promising

Compare with historical control

Wait for randomize phase III trial

Incorporate taxane

PTF better than PF

Well-tolerated (less 5FU-mucositis)

Post-op CCRT

Risk factors of post-op recurrence

Primary tumor

Positive or close margin

Neck

Multiple LN: >2

Extracapsular extension

Perineural invasion

Vascular embolism

Both locoregional and distant

Annals of Oncology 2004; 15: 1179-1186 Head and Neck 2000; 22: 680-686

Adjuvant RT

For possible residual disease

Positive margin or close margin

Multiple neck LN

Attempt to decrease local failure

Decrease subsequent distant failure

CCRT better than RT ?

Radiology 1970; 95: 185-188 Clinical Otolaryngology 1982; 7: 185-192 Head and Neck Surgery 1984; 6: 720-723 Head and Neck Surgery 1987; 10: 19-30

N Eng J Med 2004; 350: 1945-1952 EORTC 22931 167 pts, HNSCC stage III/IV XRT Cisplatin + XRT Cisplatin 100mg/m2, D1, D22, D43 XRT 54Gy/27fx, Boost 12Gy/6fx Surgery Surgery pT3/T4 + any N pT1/T2 + N2/N3 pT1/T2 + N0/N1 + unfavorable patho 80% 20% Vascular embolism 43% 57% Extracapsular spread 2% 85% 13% Perineural invasion 1% Unknown 71% Negative 28% Positive Margin 1% Unknown 22% Larynx 20% Hypopharynx 30% Oropharynx 26% Oral cavity

N Eng J Med 2004; 350: 1945-1952 EORTC 22931 0.61 25% 21% Dist Mets 0.007 31% 18% LRR 0.02 40% 53% 5yr OS 0.04 p value 36% RT 47% CCRT 5yr PFS 0.001 21% 41% Acute mucosa reaction - 16% Severe leukopenia 20% 14% Xerostomia p value 5% RT 10% CCRT Mucosa fibrosis 49% 3rd 66% 2nd 88% 1st C/T on time without delay

RTOG 9501 416 pts, HNSCC, high risk of recurrence XRT Cisplatin + XRT Cisplatin 100mg/m2, D1, D22, D43 XRT 60Gy/30fx, Boost 6Gy/3fx Surgery Surgery N Eng J Med 2004; 350: 1937-1944 83% LN>2 or extracapsular extension 17% Positive margin 21% Larynx 10% Hypopharynx 42% Oropharynx 27% Oral cavity

N Eng J Med 2004; 350: 1937-1944 45.9 months follow-up time hematological, mucosa, GI tract RTOG 9501 0.46 20% 23% Dist Mets as 1st event 0.01 30% 19% LRR 0.19 45% 52.5% OS 0.01 p value 30% RT 40% CCRT DFS 0.001 34% 77% Acute adverse effect 0.29 p value 17% RT 21% CCRT Late adverse effect

Post-op adjuvant CCRT

Decrease locoregional recurrence

Not affect distant metastasis

Though systemic side-effect

Insufficient dose delivery?

Single agent not enough?

Actually improve survival

Locoregional recurrence dominant in HNSCC

Organ preservation

Organ Preservation

Laryngeal cancer as an example

Supraglottic

Subglottic

T1: limited, not extend to glottis

T2: extend to glottis, but normal cord mobility

T3/T4: cord fixation, invade adjacent tissue

Glottic

T1a/b: limited to one/both sides, no cord fixation

T2: impair cord motility, to supra- or subglottis

T3/T4: cord fixation, invade adjacent tissue/organ

Laryngeal cancer

Historically

Early: T1, T2

RT alone, surgical salvage, or

Surgical  adjuvant RT

Larynx usually preserved

Advance: T3, T4

RT alone not sufficient

Surgical resection, usually total laryngectomy

New England Journal of Medicine 1991; 324: 1685-1690 Veterans Affairs Laryngeal Cancer Study Group 332 pts, laryngeal SCC stage III/IV Surgery Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 6600-7600cGy C/T x 1 Residual disease Poor respond 39% Laryngectomy-free survival 0.001 11% 17% Distant mets NS 8% 5% Recur at regional 0.001 12% 2% Recur at primary 0.98 68% 68% OS 0.12 p value 65% C/T  RT 75% Surgery DFS 2yr 26% T4 65% T3 9% T1/T2 63% Supraglottis 37% Glottis

QOL assessment

Veterans Affairs Laryngeal Cancer Study Group

C/T  RT vs. Surgery  RT

“pain”, “mental health”, “bother “

Laryngectomy vs. Laryngeal preserve

“pain”, “mental health”, “bother”

“role physical”, “social function”, “emotion”, “response”

No difference in speech and eating

Arch Otolaryngol Head Neck Srug 1998; 124: 964-971

Journal of National Cancer Institute 1996; 8: 890-899 EORTC 194 pts, hypopharynx SCC stage II/III/IV Surgery Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 7000cGy C/T x 1 Residual disease Poor respond 35% Laryngectomy-free survival 0.041 25% 36% Distant mets NS 19% 23% Recur at regional NS 12% 17% Recur at local NS 30% 35% OS NS p value 25% C/T  RT 32% Surgery DFS 5yr 5% T4 75% T3 20% T2 22% Aryepiglottic fold 78% Pyriform sinus

Oral Oncology 1998; 34: 224-228 GETTEC, French 68 pts, laryngeal SCC all T3 Surgery C/T x 3 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 7000cGy Inferior outcome !! 28% Unknown 41% Glottis 31% Supraglottis 42% 8yr Laryngectomy-free survival 0.006 69% 84% 2yr OS 0.02 p value 62% C/T  RT 78% Surgery 2yr DFS

New England Journal of Medicine 2003; 349: 2091-2098 RTOG 91-11 518 pts, laryngeal SCC III/IV Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w CCRT RT CCRT: RT 7000cGy/35fx Cisplatin 100mg/m2, q3w C/T x 1 Residual disease Poor respond RT alone Speech/swallow : similar 0.004(B v C) 0.001(B v A) 61% 78% 56% LR control 0.03(B v A) 15% 12% 22% Distant mets 0.005(B v C) 0.001(B v A) 75% 88% 70% Intact larynx 56% 27% A: RT NS 55% 54% OS 0.02(C v A) 0.006(B v A) p 38% C: C/T  RT 36% B: CCRT DFS 5yr 10% T4 78% T3 12% T2 31% Glottis 69% Supraglottis

Laryngeal preservation