Systemic therapy in head and neck cancers 2014 1

Systemic therapy in
Head and neck cancers
Prof Ahmed Zeeneldin
Prof of Medical Oncology
Director of Research center
Prof Ahmed Zeeneldin 2014

Many Sub-Sites
• Heterogeneous group of cancers
of varying primary sites
• 95% are SCCHN
– Lip
– Oral cavity
– Oropharynx/hypopharynx
– Larynx
– Nasopharynx
– Paranasal sinuses
– Salivary glands
SCCHN = squamous cell carcinoma of the head and neck.
Devlin et al, 2007; Ridge et al, 2009; Patel et al, 2005.

Multidisciplinary Team (MDT)
• Medical oncologists,
• Radiation oncologists,
• Head and neck surgeons,
• Plastic and/or reconstructive surgeons,
• ENT specialist
• Dentists
• Radiologists,
• Speech therapists, Social workers, psychologists

Staging Lip, Oral Cavity, oropharynx, hypopharynx, major
salivary glands 2010
T STAGE
• T1: <= 2 cm
• T2: <= 4 cm
• T3: > 4cm ( or extracapsular exten in Saliv)
• T4a: locally advanced, moderate (resectable)
• T4b: locally advanced, marked (irresectable)
N STAGE OF ALL HN CANCERS
• N1: <=3 cm single ipsilateral
• N2: <= 6cm
– N2a: single (1) ipsilateral
– N2b: multiple (>1) ipsilateral
– N2c: (=>1) contralteral (or bilateral)
• N3: > 6 cm
M STAGE
• M1 of all HN cancers: distant mets
T of Hypopharynx (HP):
• T1: <=2cm or one HP subsite
• T2: <= 4 cm, or > 1 HP subsite,
hemipharynx not fixed
• T3: > 4 cm, or fixed
hemipharynx or esophageal
invasion
STAGE GROUPING of HNC :
• I: T1 [resectable]
• II: T2 [resectable]
• III: T3 or N1 [resectable]
• IVA: T4a or N2 [LA]
• IVB: T4b or N3 [LA]
• IVC: M1 [metastatic]

Staging Nasopharyngeal Cancer 2010
T STAGE
• T1: NP, OP, nasal cavity
• T2: Parapharyngeal extension
• T3: bone of Skull base or PNS
• T4: HP, intracranial extension, cranial nerve +,
Orbit, infratemporal fossa
• NP: nasopharynx, OP: oropharynx, HP:
hypopharynx, PNS: paranasal sinus
N STAGE OF NPC CANCERS
• N1: <= 6cm single cervical LN+ (above supraclav
fossa) or any retropharyngeal LN <=6cm
• N2: <= 6cm Bilateral cervical LN+ (supraclav
fossa)
• N3: > 6 cm or supraclav fossa +
M STAGE
• M1 of all HN cancers: distant mets
STAGE GROUPING of NPC :
• I: T1 N0
• II: T2NO, T1N1, T2N1
• III: T3, N2
• IVA: T4
• IVB: N3
• IVC: M1 [metastatic]

Stage grouping
T1
2cm
T2
4cm
T3
>4 cm
T4a
+invade
T4b
++ invade
M1
N0 I II III IVA IVB IVC
N1
3cm
SIPSI
III III III IVA IVB IVC
N2
3-6 cm
IVA IVA IVA IVA IVB IVC
N3
>6cm
IVB IVB IVB IVB IVB IVC
Stage Grouping
I:T1
II:T2
III:T3, N1
IV: T4, N1-2, M1
IVA: T4A, N2
IVB: T4B, N3
IVC: M1

Classification
T1
2cm
T2
4cm
T3
>4 cm
T4a
+invade
T4b
++ invade
M1
N0 EARLY Locally advanced
Metastatic
N1
3cm
SIPSI
Locally advanced
N2
3-6 cm
N3
>6cm
• Very advanced HNC:
• T4b
• unresectable N
• unfit for surgery Prof Ahmed Zeeneldin 2014

Surgical resectability
T1
2cm
T2
4cm
T3
>4 cm
T4a
+invade
T4b
++ invade
M1
N0 I, II
EARLY
Resectable
III-IVB
Locally advanced
IVC
Met
CTIII
??Resectable
IVA
??
IVB
Irresectable
N1
3cm
SIPSI
III
Locally advanced
Resectable
As above
N2
3-6 cm
IVA
Locally advanced
??? Resectable
N3
>6cm
IVB
Locally advanced
?? Irresectable

Treatment
T1
2cm
T2
4cm
T3
>4 cm
T4a
+invade
T4b
++ invade
M1
N0 EARLY
Resectable
S=RT
Locally advanced IVC
Met
CT
Resectable
CRT
??
CRT
Irresectable
CRT
N1
3cm
SIPSI
Locally advanced
Resectable
S, CRT
As above
N2
3-6 cm
Locally advanced
??? Resectable
CRT
N3
>6cm
Locally advanced
Irresectable
CRT

Treatment of Early HNC
Stage I and II
• T1 and T2 tumors (up to 4 cm, N0).
• ~40% of cases
• Single Modality:
– Surgery or RT (NOT CRT)
• Equally effective: 60%-90% cure rate
– According to site and extensions
• NO ADJUVANT therapy
• Each modality can salvage the other if local
recurrence

Treatment of Early HNC
Stage I and II
• Choice depends on
– Tumor: site, extension
– Patient: preference, comorbidities,
– Expertise of the multidisciplinary
team, available equipment
• RT in:
– lip, retromolar trigone, and soft palate
– Nasopharynx
– Larynx
– Surgery intolerable or refused

Surgery in HNC
• Surgery:
– T1, T2 >T3 > T4a
– N0 > N1 > N2
• Aim:
-Resect all gross tumors with adequate SM
• Surgical procedure, margins, and reconstructive plan are
based on oncologic aim
• Planned based on initial presentations and not on response
to preoperative therapy (unless progression)

Poor respectability outcomes
• Superior NP+, lateral NP walls+,
Eustachian tube +
• Skull base +
• Pterygoid muscles invasion (+)
• Common or internal carotid A
+ or 270 degree encasement
• Skin+, subdermal mets
• Mediastinal +
• Cervical vertebrae or prevertebral fascia

Treatment of Metastatic disease (M1)
Stage IVC
• 20%-30% of HNC develop metastases
• Included here are recurrences that can’t be salvaged by
– surgery or re-irradiation
• Systemic therapy
– 1Single agent CT Increases OS by 10 weeks than BSC
– Chemotherapy:
• Single agent chemotherapy
• Combination chemotherapy
– Platinum
– Platinum-taxane
– Targeted therapy (MCAB, TKI):
• In combination with chemotherapy
• alone
1Cancer Chemotherapy and Pharmacology, 1985, 15(3):283-289

Treatment of Metastatic disease (M1)
Stage IVC
• Treatment choice depends on:
– performance status (PS),
– co-morbidity,
– prior treatment,
– symptoms,
– patient preference
– logistics
• Goals of treatments
– Symptom control
– Good quality of life
– Tumor response/stabilization
– Increase survival

Chemotherapy in RM HNC
• Predictors of poor OS with platinum-based CT
Analysis of TWO ECOG trials E1395 and E1393
Cancer. 2004 Nov 15;101(10):2222-9.

Chemotherapy in RM HNC
• 5 Predictors of
poor OS with
platinum-based CT
– Pathologic:
• 1. well diff. tumors
– Clinical:
• 2. ECOG PS >0,
• 3. Weight loss >5%
• 4. Site: HP, mouth
• 5. Prior RT

Predictors of poor OS with platinum-
based CT in HNC
• 0-2 :
– Median OS 12 months
• 3-5:
– Median OS 6 months
• Response to chemotherapy
nullified the site impact
• Long term survivors (3.6%) @
5 years had recurrent but not
metastatic disease

Single agent chemotherapy
• Older agents:
– Methotrexate, cisplatin, 5-ﬂuorouracil (5-FU) and
bleomyin
– RR 15-30% of short duration and rare CRs
• Newer agents:
– Taxanes (paclitaxel and docetaxel)
pemetrexed, vinorelbine, irinotecan, capecitabine,
S-1
– Taxanes:
• RR 20-40%

Comparisons of single agents
Mtx cisplatin
p
No 22 22
Dose 40-60 mg/m q W 50 mg/m d1,8 q4W
RR 24% 29% 0.51
Duration of
response
84 days 92 days
Median OS 6.1 m 6.3 m NS
Toxicity Mucositis (40%) Vomiting (90%)
Cancer. 1983 Jul 15;52(2):206-10.

Mtx Cisplatin p
No 50 50
RR 16% 8%
Duration of
response
18 W 8 W
Median OS 5 M 4.5 M
Cancer Treat Rep. 1985 Jun;69(6):577-81.

Mtx Docetaxel p
No 20 37 (2:1
randomization
Dose 40 mg/m/w 40 mg/m/w
RR 15% 27%
TTP Similar Similar
OS Similar Similar
Eur J Cancer. 2004 Sep;40(14):2071-6.

Single agent vs. platinum doublets
PF CF Mtx P
Dose (q3w) P:100mg/m d1
F: 1000mg/md1-4
Cb:300mg/m d1
F: 1000mg/md1-4
40 mg/m/w
RR 32% 21% 10% <0.05
Response duration NS
Overall survival 6.6 M 5.0 M 5.6 M NS
Toxicity Higher intermediate Lower 0.001
J Clin Oncol 1992; 10: 1245–1251.

• Combination:
– Higher RR
– Similar OS
– Cisplatin better than carboplatin

Chemotherapy doublets:
Platinum-taxane vs. platinum-non-taxane
CF CP P
No 106 108
Dose P: 100 mg/m d1
F: 1000 mg/m
d1-4
T:175 mg/m 3h d1
P: 100 mg/m d1
ORR (CR) 29.8% (7%) 26% (7%) NS
Median
OS
8.7 M 8.1 M NS
Toxicity
G3/4
Similar Similar NS
Higher
mucositis
Considering the more favorable toxicity proﬁle, CP (cisplatin-
paclitaxel) may be a valuable alternative to PF.
J Clin Oncol 2005; 23: 3562–3567Prof Ahmed Zeeneldin 2014

Three-drug taxane-platinum combinations
DCF
No 16
Dose (q 28 d) Docetaxel: 80 mg/m D1
P: 40 mg/m d1, 2
F: 1000 mg/m d1-3
ORR (CR) 44% (12.5%)
TTP 7.5 M
Median OS 11 M
Growth factor D4-8
Febrile neutropenia 15%
Am J Clin Oncol. 2000 Apr;23(2):128-31.

DIP
No 22
Dose (q 21 d) Doce: 60-75 g/m d1
Ifo + mesna: 1000 mg/m ICI d1-5
P: 50-75 mg/m d1 OR 5
ORR (CR) after 2 cycles 95% (5%)
CR after 4 cycles 42%
RFS 13.8 M
Median OS 18.8 M
Grade 4 neutropenia 82%
Toxic death 5%
J Clin Oncol 2005; 23: 3562–3567

TIP1 TIC2
No 22 55
Dose (q 21-28 d) pacli: 175 mg/m d1
Ifo + mesna: 1000 mg/m 2h d1-3
P: 60 mg/m d1
pacli: 175 mg/m d1
Ifo + mesna: 1000 mg/m 2h d1-
Carb: AUC 6 d1
ORR (CR) 58% (17%) 59% (17%)
Response duration 15.7 M 9.7 M
Median OS 8.8 M 9.1 M
Febrile neutropenia 27% 30%
GCSF Not allowed Not allowed
Higher response rates BUT also higher complication rate
1J Clin Oncol 2005; 23: 3562–3567
2Cancer 2001; 91: 1316–1323.

Recommendations
• Combinations (doublets) are indicated on
– younger patients with good PS and with
symptomatic disease who require prompt
symptom relief.
• Triplets are very toxic and should only be used
in clinical trials

Targeted therapies
• Classes:
– mAB : cetuximab (not panitiumumab)
– EGFR TKI: Affatinib
• Use:
– Single
– In combination with chemotherapy

Targeted therapy
Cetuximab single agent
• As second line after failure of platinum-based
therapy
• Loading: 400 mg/m followed by weekly 250
mg/m
• Response:
– RR: 10-13%
– DC: 45-55%
• OS: 5-6 months (vs. 2.5 months oh historical
controls)

Targeted therapy
Cetuximab + chemotherapy
• As first-line therapy
• Loading: 400 mg/m followed by weekly 250 mg/m
EXTREME STUDY: Cetuximab and platinum-based chemotherapy is now
considered as a new standard for the treatment of R/M-SCCHN for those who
are able to tolerate platinum-based combination chemotherapy regimens
N Engl J Med 2008; 359: 1116–1127.Prof Ahmed Zeeneldin 2014

Targeted therapy
Cetuximab + Cisplatin
DDP DDP-cetux p
No 60 57
Dose (q
4W)
P:100 mg/m
D1
P: 100 mg/m D1
Cet: 200 mg/m w1
125mg/m/w
ORR (CR) 10% 26% 0.03
PFS 2.7 M 4.2 M NS
Median OS 8 M 9.2 M NS
Toxicity Skin
Cetuximab dose used is LOW
J Clin Oncol 2005; 23: 8646–8654.

Targeted therapy
Cetuximab + PF doublet
PF PF+ cetux P
No 220 222
Dose (q
3W)
Cis/carbo Cis/carbo +
Cetux
ORR (CR) 20% 36% <0.001
TTF 3 M 4.8 M <0.001
PFS 3.3 M 5.6 M <0.001
Median OS 7.4 M 10.1 M 0.04
Cis: 100 mg/m d1
Or carbo AUC 5 d1
FU 1000 mg/m d1-4
+/- Cetux: 400 mg/m W1
250 mg/m/w
N Engl J Med 2008; 359:1116-1127
EXTREME STUDY

Targeted therapy
Panitumumab+ chemotherapy
CF CF+ Pan P
No 330 327
Dose (q 3W) Cis/carbo Cis/carbo +
Pan
ORR (CR)
TTF
PFS 4.6 M 5.8 M 0.004
Median OS: all
P16 negative
9 M
8.6 M
11.1 M
11.7 M
0.14
0.01
Cis: 100 mg/m d1
FU 1000 mg/m d1-4
+/- Panitumumab: 9 mg/ kg d1
Lancet Oncology, 2013: 14(8) 697 - 710,
SPECTRUM STUDY

Targeted therapy
Afatinib vs. Cetuximab
Afatinib cetuximab
No 74 74
Dose 50 mg/d 400->250 mg/m/w
ORR (CR) 21.7% 13.3%
SD 53% 50%
PFS 16 W 10 W
J Clin Oncol 2010; 28 (15 Suppl): Abstr 5501.
Currently:
Affatinib vs. Mtx in RM HNC
Adjuvant after CCRT

Treatment
T1
2cm
T2
4cm
T3
>4 cm
T4a
+invade
T4b
++ invade
M1
N0 Locally advanced
Resectable
CRT>S
??
CRTàS
Irresectable
CRT
N1
3cm
SIPSI
Locally advanced
Resectable
S, CRT
As above
N2
3-6 cm
Locally advanced
??? Resectable
CRTàS
N3
>6cm
Locally advanced
Irresectable
CRT

Treatment of locally advanced HNC
Stage III-IVB: T3-4ab, N1-3
• LA resectable: T3, N1
– Surgery
– CRT
• LA irresectable: T4b, N3
– Induction chemo à surgery or RT/CRT
– Induction chemoà surgery à ? RT/CRT
– Induction chemo à RT/CCRT à ? Surgery
– CCRTà? Surgery
• LA ?? Resectable: T4a, N2
– ?? As irresectable
Resectable ?? Irresectable
T3 T4a T4b
OR OR OR
N1 N2 N3
Surgeryà±RT/CRT
CRTà±Surgery
ICTàCRT

Treatment modalities in LA HNC
• RT
• Induction chemotherapy (IC) + RT
• Concurrent Chemo-RT (CCRT)
• Sequential TX (IC + CCRT)

RT vs. CCRT in unresectable LA HNC
Intergroup E1392 trial
• De no vo unresectable LA SCC HNC
– Exclude NPC, paranasal Sinus, Parotid
• 3 arms:
– Arm A: Radiation (70 Gy) alone on daily doses of 2 Gy.
– Arm B Radiation (as above ) concurrent with 3 cycles of P
cisplatin 100 mg/m D1, D22 and D43 (q 21 d).
– Arm C: Split course radiation concurrent with 3 cycles of PF
(4 day CIVI 5-FU 1000 mg/m with cisplatin 75 mg/m2 on D1[q 28 d]). (30 Gy with
first two cycles and 30–40 Gy with third cycle)
J. Clin. Oncol. 21(1), 92–98 (2003).

RT alone RT+Cis Split RT + PF P
N 95 87 89
CR 27.4%* 40.2% 49.%* 0.002
Surgery (%) 19% 24% 23% NS
3 –y DFS 33%* 51%* 41% 0.01
3-y OS 23%* 37%* 27% *0.014
Median OS 12.6 M* 19.1 M* 13.8 M *0.014
Toxicity G≥3 52% 89% 77%
CCRT is standard in LA
unresectable SCC HN
J. Clin. Oncol. 21(1), 92–98 (2003).

RT vs. weekly cis CCRT in unresectable LA HNC
Intergroup E2382 trial
• De no vo unresectable LA SCC HNC
– Exclude NPC, paranasal Sinus, Parotid
• 3 arms:
– Arm A: Radiation (70 Gy) alone on daily doses of 2 Gy.
– Arm B Radiation (as above ) concurrent with WEEKLY
cisplatin 20 mg/m D1, 8,15,22,29,36,43).
Int J Radiat Oncol Biol Phys. 2011; 81(3): 719–725.

RT alone RT+ W Cis P
N 159 149
CR 37% 40% 0.64
OR 67% 79% 0.03
Median EFS 6.5 M 7.2 M 0.3
Median OS 13.3 M 11.8 M 0.81
Toxicity G≥3 Higher
CCRT with weekly
cisplatin in unresectable
LA SCC HN is not
recommendedProf Ahmed Zeeneldin 2014

cisCCRT weekly (40mg/m) vs 3 weekly (100mg/m)
Tsan et al. Radiation Oncology 2012, 7:215Prof Ahmed Zeeneldin 2014

Higher toxicity with weekly cis 40 mg/m

Similar OS and LRFS
• Conclusions: compared to weekly low-dose cisplatin CRT,
Three-weekly high-dose cisplatin CRT showed
– higher compliance, and
– lower acute toxicity.

Treatment of LA HNC
• Conclusion 1
– CCRT better than RT alone
– Cisplatin is better than carboplatin
– Cisplatin 100 mg/m D1, 22, 43 better than weekly
doses whether 20 mg/m or 40mg/m

RT Alone vs. Concomitant P+RT Vs. Induction PFàRT
in Resectable glottic or surpraglottic SCCHN
(organ preservation): RTOG 91-11 Trial
Forastiere et al, 2003, 2006.
Resectable Stage III/IV
SCCHN
v Glottic or supraglottic
cancer
v Previously untreated
N = 515
Cisplatin (100 mg/m2, D1)
5-FU (1,000 mg/m2/d, D1–5)
q3wks, 2-3 cycles
CRT (n = 171)
R
A
N
D
O
M
I
Z
E
ICT à RT (n = 173)
Cisplatin (100 mg/m2 q3wks, 3 cycles)
RT (as above)
RT (2 Gy/fr, 35 fr, total 70 Gy)
RT (n = 171)
RT
(as
abovr)
v Primary end point: Larynx preservation
– Secondary end point: LFS
LFS = laryngectomy-free survival; ICT = induction chemotherapy.

RT CCRT ICàRT P
N 171 171 173
CR to ICT 21%
CR-completion 148 (87%) 154 (90%) 150 (87%)
Laryngeal preservation 67%* 84%* 72%* CCRTvs RT & IC : S
ICT vs RT: NS
2y- LFS
5-y LFS
53%*
33.9%*
66%*
46.6%*
59%
44.6%
0.01
0.011
2-y DFS
5-y DFS
44%
27.3%
61%
39%
52%
38.6%
CCRT vs RT =0.006
ICT vs RT = 0.02
2-y Local control
5-y Local control
58%
51%
80%
68.8%
64%
54.9%
CCRT vs RT & ICT: S
ICT vs RT: NS
2-y Distant metastases
5-y Distant metastases
16%*
22.3%
8%*
13.2%
9%
14.3%
0.03
0.06
2-y OS
5-y OS
75%
53.5%
74%
54.6%
76%
59.2%
NS
RT vs. CCRT vs. ICTàRT in organ preservation

Larynx Preservation
Forastiere et al, 2003.

RTOG = Radiation Therapy Oncology Group.
Forastiere et al, 2006.
RTOG 91-11 Results: LFS and OS
Alive(%)
0 1 2 3 4 5 6 7 8 9 10
LFS
AliveWithoutLaryngectomy(%)
100
75
50
25
0
Time (yrs from randomization)
OS
Time (yrs from randomization)
100
75
50
25
0 0 1 2 3 4 5 6 7 8 9 10
RT + induction
RT + concomitant
RT alone

Organ Preservation
Laryngeal Cancer
• Compared with RT alone, LFS significantly better with
– ICT followed by RT
– RT/concurrent cisplatin
• Compared with ICT followed by RT or RT alone
– Laryngeal Preservation and locoregional control significantly better
with RT/concurrent cisplatin
• No significant difference in OS
• CRT now the standard of care in organ preservation

Conclusions of the prior two studies
• Chemoradiotherapy (concomitant or
sequential) is better than RT alone in
irresectable HN cancer and resectable glottic
or supraglottic cas
• CCRT is better than SCRT in laryngeal
preservation
• SCRT is not significantly inferior to CCRT in
irresectable HNca

Meta-analysis of chemotherapy added to locoregional
Tx (surgery/RT) in HNSCC:
MACH-NC
• 2000:
– 63 trial (10 741 patients) between 1965-1993
– oropharynx, oral cavity, larynx, or hypopharynx
• 2007 update:
– 63 +24 trials (87 trials) (16 665 patients) between 1965
and 2000
– oropharynx, oral cavity, larynx, or hypopharynx,
Nasopharynx
• 2009 update
• 2011:
– Site analysis

Meta-analysis of chemotherapy added to locoregional
Tx (surgery/RT) in HNSCC: MACH-NC, 2000
• Between 1965 and 1993, 63 trials (10 741 patients) of locoregional treatment with
or without chemotherapy in oropharynx, oral cavity, larynx, or hypopharynx
• † Two trials with three arms (control, neoadjuvant, and concomitant chemotherapy) were
included both in neoadjuvant and concomitant comparisons and appear twice in table.
• Adjuvant: locoregional Tx (S/RT)à CTx
• Noadjuvant: CTx (induction) à locoregional Tx (S/RT)
• Concomitant: CTx+RT
Lancet 2000; 355: 949–55Prof Ahmed Zeeneldin 2014

MACH-NC, 2000
• Induction/Neoadjuvant PF (not other regimens)
– significantly improved OS (HR 0.88, 95% CI 0.79–0.97)
– 15 trials with 2,487 patients:

MACH-NC, 2007 update
• Between 1965 and 2000, 63 +24 trials (87 trials) (16 1665patients) of
locoregional treatment with or without chemotherapy in oropharynx, oral cavity, larynx, or
hypopharynx, Nasopharynx
• The direct comparison showed that concomitant chemotherapy had a better effect (though
not signiﬁcantly so) than neoadjuvant chemotherapy (HR = 0.90; 95% CI 0.77–1.04; p =
0.15)
• This was also confirmed in Naspoharyngeal Cancer
Int. J. Radiation Oncology Biol. 2007 Phys.,69 (2):S112–S114

Effect of age
Int. J. Radiation Oncology Biol. 2007 Phys.,69 (2):S112–S114 Prof Ahmed Zeeneldin 2014

Radiotherapy and Oncology 92 (2009) 4–14
OS gain @ 5-Y 6.5%
HR of Death 0.81 (95% CI: 0.78–0.86)
(p < 0.0001)
OS gain @ 5-Y 2.4%
HR 0.99 [0.93;1.05]
P>0.05
OS Loss @ 5-Y 1%
HR 0.99 [0.89;1.10]
P>0.05
Similar results were observed for event-free survival,

concomitant CTX agent

CCRRT vs induction (indirect comparisons)
• overall survival benefit CCRT > ICTàRT: 3.5% increase @ 5y
• Locoregional failure CCRT better: 9.3% reduction @ 5y
• Distant failure IC better: 4.3% reduction @5y

CCRRT vs induction (PF regimen)
• CCRT with PF: 13.5% reduction in local failure @ 5y
• IC with PF: 3.5% reduction in distant failure @ 5y

prognostic factors
CCRT not to be used in
• Stage I, II
• PS >1
• Older Age
• Site??

Site analysis
• OS is better in all sites with CCRT only

Site analysis
• PFS is better in all sites with CCRT

Phase III Trial of TPF àRT Vs. PFàRT
TAX 323
Response (ICT + RT) TPF (n = 177; %) PF (n = 181; %) p Value
CR (ICT + RT) 33.3 19.9 .004
PR (ICT + RT) 39.0 38.7 NR
SD (ICT + RT) 13.6 21.5 NR
PD (ICT + RT) 6.2 7.2 NR
ORR (ICT + RT) 72.3 58.6 .0063
Treatment-Naïve
Unresectable
Stage III/IV SCCHN
v Excluding nasopharynx,
nasal, and paranasal
cavities
v Uni- or bidimensionally
measurable disease
v WHO PS 0/1
v Adequate hematologic,
hepatic, and renal function
N = 358
R
A
N
D
O
M
I
Z
E
Docetaxel (75 mg/m2, D1)
5-FU (750 mg/m2/d, D1–5, C1)
q3wks, 4 cycles
5-FU (1,000 mg/m2/d,
D1–5, C1)
q3wks, 4 cycles
Conventional daily RT
(1.8–2.0 Gy/d, 5 d/wk,
total 66–70 Gy)
or
Accelerated/
hyperfractionated RT
(twice daily, 5 d/wk,
total 70–74 Gy)
ICT RT
WHO = World Health Organization; CR = complete response; F = 5-fluorouracil; ORR = overall response rate; NR = not reported;
P = cisplatin; PD = progressive disease; PR = partial response; SD = stable disease; T = docetaxel; EORTC = European
Organization for Research and Treatment of Cancer; TPF = cisplatin, fluorouracil, docetaxel.
Vermorken et al, 2007.

TAX 323
PFS TPFàRT PFàRT
Median PFS 11.0 M 8.2 M
HR (95% CI) 0.72 (0.57–0.91)
p Value .007
OS TPFàRT PFàRT
Median PFS 18.8 M 14.5 M
5-y OS 27.5% 18.6%
HR (95% CI) 0.73 (0.56–0.94)
p Value .02
v TPFà RT improves RR, PFS, and OS compared with PFà RT
PFS = progression-free survival; RR = response rate.
Vermorken et al, 2007, 2004; Remenar et al, 2006.

Chemotherapy- and
RT-Naïve Stage
III/IV SCCHN
v Oral cavity,
oropharynx,
hypopharynx,
larynx
N = 501
R
A
N
D
O
M
I
Z
E
Cisplatin (100 mg/m2)
5-FU (1,000 mg/m2/d, D1–5)
q3wks, C1 3 cycles
Carboplatin
(AUC 1.5
weekly)
Daily RT
(5 d/wk)
ICT CRT
Docetaxel (75 mg/m2)
Cisplatin (100 mg/m2)
5-FU (1,000 mg/m2/d,
96-hr C1)
q3wks, 3 cycles
Phase III Trial of TPFè CRT Vs. PFè CRT
Sequential Therapy in Advanced SCCHN
TAX 324
Response
TPF
n = 255 (95% CI)
PF
n = 246 (95% CI)
p Value
ORR (ICT) 72% (65.8–77.2) 64% (57.9–70.2) .07
CR (ICT) 17% (12.1–21.6) 15% (10.8–20.1) .66
ORR (ICT + CRT) 77% (70.8–81.5) 72% (65.5–77.1) .21
CR (ICT + CRT) 35% (29.4–41.5) 28% (22.5–34.1) .08
AUC = area under the curve.
Posner et al, 2007.

TAX 324: Results
v TPFàCRT significantly improves OS and PFS compared with PFàCRT
Posner et al, 2007.
TPF 62%
PF 48%
TPF 67%
PF 54%
Log-rank p = .0058
HR = 0.70
TPF 53%
PF 42%
TPF 49%
PF 37%
Log-rank p = .004
HR = 0.701
Survival PFS
Time (mos)
SurvivalProbability(%)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 255)
PF (N = 246)
Time (mos)
PFSProbability(%)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (N = 255)
PF (N = 246)

Posner et al, 2007.
TAX 324: Toxicity
Grade 3/4 Toxicity TPF (%) PF (%)
Stomatitis 21 27
Nausea 14 14
Lethargy 5 10
Vomiting 8 10
Diarrhea 7 3
Anorexia 12 12
Neutropenia 84 56
Febrile Neutropenia 12 7
Neutropenic Infection 12 9
Stomatitis 37 38
Dysphagia 23 24
Mouth, Nose Dryness 5 4
Nausea 6 6
Rash/Itch 5 2
During ICT
N = 251 TPF,
243 PF
During CRT
N = 203 TPF,
184 PF

Chemotherapy- and
RT-Naïve Stage
III/IV SCCHN
v Oral cavity,
oropharynx,
hypopharynx,
v
NOT larynx
N = 101
R
A
N
D
O
M
I
Z
E
Same CRT
Cisplatin (80mg/m2)
5-FU (800 mg/m2/d, d1-4)
q3wks, 3 cycles
Phase II Trial of TPFè PF/CRT vs. PF/CRT
Radiologic Response
TPFàPF/CRT
n = 50
PF/CRT
n = 51
p Value
CR TPF 6.5%
CR CRT 50% 21.3% 0.004
Surgery for rad/clinical residual 19.5% 38.2% 0.047
Cis 20 mg/m/d d1-4
FU 800mg/m/d d1-4 W1 & W6 of
Daily RT (5 d/wk 70 GY)

TPF/ICTàPF/CRT vs. PF/CRT
v Despite no significant OS or PFS benefit, the
study was underpowered to detect such
differences
Ann. Oncol. 21(7), 1515–1522 (2010)

Phase III Sequential Therapy Trials in
North America: Paradigm
QOL = quality of life.
US NIH, 2010a.
Paradigm
Stage III/IV SCCHN
v Oral cavity,
oropharynx,
hypopharynx, larynx
Expected N = 330
R
A
N
D
O
M
I
Z
E
Docetaxel
Cisplatin
5-FU
q3wks,
3 cycles
Docetaxel (q1wk for 4 wks)
Once/twice-daily RT (D1–5)
6 wks
Carboplatin (q1wk)
Daily RT (D1–5)
7 wks
Cisplatin (Wks 1, 4)
6 wks
CR
PR
ICT CRT
v Primary end point: 3-yr survival
v Secondary end points: 2-, 3-, and 5-yr PFS, 5-yr survival, CR,
tumor site-specific survival, functional organ preservation, toxicity,
QOL, tissue and germline biomarkers

Chemotherapy- and
RT-Naïve Stage
III/IV SCCHN
v Oral cavity,
oropharynx,
hypopharynx,
v larynx
N = 145
R
A
N
D
O
M
I
Z
E
Cisplatin (80mg/m2)
5-FU (800 mg/m2/d, d1-4)
q3wks, 3 cycles
Phase II Trial of TPF è D or Cb/CRT vs. cis/CRT
Paradigm trial
Radiologic Response
TPF—CRT
n = 70
Cis/CRT
n = 75
p Value
3-y OS rate 73% 78% 0.77
3-y PFS 67% 73% 0.55
RT: Daily RT (5 d/wk 70 GY)
Cis 100mg/m/d d1-29
RT with either
Carboplatin weekly
Docetaxel weekly
Clin. Oncol. 28(Suppl. 15), Abstract 5563 (2010).

Phase III TPFàCRT vs. CRT
North America: DeCIDE
DeCIDE
Chemotherapy and
RT-Naïve SCCHN
N2/N3 disease
Expected N = 400
R
A
N
D
O
M
I
Z
E
v Primary end
point: OS
v Secondary end
points: Distant
FFS, failure
pattern, PFS,
QOL
ICT-CRT CRT P value
Distant Mets 10% 19% 0.025
3-y OS 75% 73% 0.7
(Abstract 550). 2012 ASCO Annual Meeting. (2012).
Docetaxel
Cisplatin
5-FU
q3wks,
3 cycles
Docetaxel (q1wk for 4 wks)
6 wks
Carboplatin (q1wk)
Daily RT (D1–5)
7 wks
Cisplatin (Wks 1, 4)
6 wks
ICT CRT

Phase III Trial of PCFàcisCRT Vs. CFàcisCRT
Treatment-Naïve
Stage III/IV SCCHN
v Excluding nasopharynx,
nasal, and paranasal
cavities
v Uni- or bidimensionally
measurable disease
v WHO PS 0/1
v Adequate hematologic,
hepatic, and renal function
N = 358
R
A
N
D
O
M
I
Z
E
Paclitaxel (175 mg/m2, D1)
Cisplatin (100mg/m2, D1)
5-FU (500mg/m2/d, D2–6, C1)
q3wks, 3 cycles
5-FU (1,000 mg/m2/d,
D1–5, C1)
q3wks, 3 cycles
(2.0 Gy/d, 5 d/wk, total 70 Gy)
Cisplatin 100 mg/m D1, 22,
43
ICT CRT
J. Clin. Oncol. 23(34), 8636–8645 (2005).
(2.0 Gy/d, 5 d/wk, total 70 Gy)
Cisplatin 100 mg/m D1, 22,
43

Phase III Trial of PCFàcisCRT Vs. CFàcisCRT
Response
(ICT + RT)
CFàcisCRT
(n = 193)
PCFàcisCRT
(n = 189)
p Value
CR (ICT) 14% 33% <.001
CR (ICT + CRT) 78% 88% NS
Time to TX failure 12 M 20 M 0.006
Median OS 37 M 43 M 0.06
Median OS
(unresectable)
26 M 36 M 0.04
Mucositis >G1 53% 16%

Phase III Trial of PCF àcisCRT Vs. CFàcisCRT

GORTEC 2000-01 Trial of Docetaxel/Cisplatin/5-FU
Vs. Cisplatin/5-FU ICT for LP in Hypopharynx and
Larynx Cancer
GORTEC = Groupe Oncologie & Radiotherapie de la Tete Et du Cou.
Pointreau et al, 2009.
Treatment-Naïve
Resectable Larynx
or Hypopharynx
Cancer
Requiring total
laryngectomy
N = 220
R
A
N
D
O
M
I
Z
E
Docetaxel (75 mg/m2, D1)
5-FU (750 mg/m2, D1–5, C1)
q3wks, 3 cycles
n = 110
5-FU (1,000 mg/m2, D1–5, C1)
q3wks, 3 cycles
n = 103
ICT
Surgery
Postop RT
(50–66 Gy)
RT (70 Gy)
Response defined as CR at
primary site or PR and
recovered normal larynx
mobility
v Outcomes: 3-yr LP rate, acute toxicities, ORR

p = .11
DFS
p = .57
OS
p = .03
LP
GORTEC 2000-01: Results
Outcome at 3 Yrs TPF (%) PF (%) p Value
Larynx Preservation rate 70.3 57.5 .03
DFS 58 44 .11
OS 80 60 .57

GORTEC 2000-01:
Response and Toxicity
Selected Acute Toxicities TPF (%) PF (%)
Alopecia (grade 2) 19 2
Stomatitis (grade 3/4) 4.6 7.8
Neutropenia (grade 4) 31.5 17.6
Febrile Neutropenia (grade 3) 10.9 5.8
Thrombocytopenia (grade 3/4) 1.8 7.8
Creatinine (grade 4) 0.0 2.0
TPF (%) PF (%) p
LP rate 70.3 57.5 .03
CR 41.8 30.1 NR
PR 38.2 29.1 NR
CR + PR 80.0 59.2 .002
v ICT with TPF in locally advanced larynx and hypopharynx cancer
leads to a significantly higher RR compared with ICT with PF
v ICT with TPF leads to a higher incidence of grade 4 neutropenia, but
is otherwise well tolerated
v ICT with TPF significantly increases 3-yr LP rate

Targeted therapy in LA HNC
v Cetuximab
v Panitumumab
v TKI afatinib?

Phase III Study of Cetuximab + RT for
Locoregionally Advanced SCCHN
N = 424
v Locoregionally
advanced
SCCHN
v Treatment naive
v KPS 60%–
100%
Cetuximab, 400 mg/m2, Wk 1
+ 250 mg/m2 qwk, Wks 2–8
+ RT, Wks 2–8a
n = 211
RTa Alone
n = 213
aInvestigators’ choice of conventional fractionation to 70 Gy, twice daily fractionation to 72–76.8 Gy, or concomitant boost to 72 Gy.
KPS = Karnofsky Performance Status.
Bonner et al, 2006a.
R
A
N
D
O
M
I
Z
E
End points
v Duration of disease control
v OS, PFS, RR, Safety

Cetuximab + RT Vs. RT Alone:
Locoregional Control
aLocoregional control and death combined.
Bonner et al, 2006a.
100
80
60
40
20
0
Time (mos)
RT plus cetuximab
LocoregionalControl(%)
RT
0 10 20 30 40 50 60 70
Cetuximab
w/RT
RT
Alone
HRa
(95% CI) p Value
Duration
of control
(mos)
24.4 14.9
0.68
(0.52–0.89)
.005

Cetuximab + RT in Locoregionally
Advanced SCCHN: OS
Bonner et al, 2006a, 2006b, 2010.
100
80
60
40
20
0
0 10 20 30 40 50 60 70
RT
Time (mos)
RT + cetuximab
OS(%) RT + Cetuximab RT Alone
HR
(95% CI)
p Value
2-yr 62% 55%
3-yr 55% 45%
5-yr 46% 36%
Median OS 49.0 M 29.3 M
0.74
(0.57–0.95)
.03

Cisplatin versus cetuximab plus concomitant RT
in LA HNC: A meta-analysis
v 5 trials (1,808 patients)
v Conclusions: Platinum-based CTRT still
remains the standard of care in LAHNC until
prospective trials can demonstrate equivalence.
Endpoint CTRT RT + CET
Risk ratio (95%
CI) P value
2-yr OS 71 % 60.7 % 0.66 (0.46-0.94) 0.02
2-yr DFS 61.7 % 43.1 % 0.68 (0.53-0.87) 0.002
2-yr LRR 19.6% 32.3% 0.63 (0.45-0.87) 0.005
Distant Mets Same Same 1.01 (0.69-1.48) 0.94
J Clin Oncol 32:5s, 2014 (suppl; abstr 6014)

v Chemoradiation is the standard of care for
locally advanced SCCHN.
v Definitive CRT remains the standard of care
despite the potential risk of distant failure
when compared with a sequential approach
v In patients that cannot undergo this treatment
modality, radiotherapy plus cetuximab
constitutes an appropriate alternative.

Adjuvant treatment after upfront surgery
in resectable HNC
v Adjuvant CCRT following surgery
– T: Positive surgical margins
– N: Extracapsular nodal spread
v Adjuvant RT or CRT following surgery
– T: Oral cavity or oropharyngeal primary
with positive level 4 or 5 nodes
– T: pT3 or pT4 primary, and
– N: Multiple positive nodes (without extracapsular nodal spread),
– N: Vascular/lymphatic/perineural invasion,
v NB: Adjuvant chemotherapy (CF) Following CRT of NPC
– T: T2-4
– N: N1-3

Treatments following CRT in LA HNC
– CR (tumor and nodes):
• follow up
– Residual (PR, stabilization or progression):
• Resectable: surgery to T and or N
– R0 in T and N: follow-up
– R1/R2: ? as metastatic disease
• Unresectable: as metastatic disease

Treatments following induction therapy
in LA HNC
v CR @ T and N:
– RT
v CR @ T only
– RT then assess N
• CR: follow up
• Residual: Node dissection
v PR @ T
– RT or CCRT and then reassess
• CR @ T and N: follow up
• Residual @ T and/or N: surgery for T and/or N
v SD or PD @ T
– Surgery
• Post op RT or CRT

Nasopharynx
v Surgery for primary tumor not feasible
v T1N0:
– RT
v >T1, >N0 (T2-4, N1-3):
– CCRT
– Surgery to N residual
– Adjuvant chemotherapy (PF x 6 cycles)
v M1:
– PF chemotherapy
– ±RT/CRT: as indicated

Salivary gland tumors
v T1 and T2
– Surgery for T
– Adjuvant RT if :
• Adenoid cystic
• Intermediate or high grade
• Low grade + perineural invasion or tumor spillage
v Resectable T3, T4a :
– Surgery for T and N
– Adjuvant RT/CRT if :
• Adenoid cystic (RT)
• Intermediate or high grade
• N+, lymphatic/vascular/perineural invasion
• SM+ or close

Salivary gland tumors
vunresectable T3, T4a AND T4b
– RT/CRT
v M1 disease
– Ps 0-2:
• Chemotherapy
• Selected metastatectomy
• Expectant management in slowly growing tuomrs
– PS 3-4:
• BSC

Summary
v Stage I and II (early HNC)
– Surgery = RT (not CCRT)
– RT in NPC and larynx
– No adjuvant therapy
v Resectable stage III (T1N1, T2N1)
– CRT
– Surgery
• Adjuvant RT/CRT in
– T: SM+,
– T: Oral cavity or oropharyngeal primary with positive level 4 or
5 nodes
– N: capsular invasion...
– N: Vascular/lymphatic/perineural invasion,

Summary
v Stage III-IVB (locally-advanced HNC)
– Include T3, T4, N2, N3
– Standard of care is CCRT
– Cisplatin better than carboplatin
– 3-weekly (100mg/m d1,22, 43) better than weekly (20 or 40
mg/m/w)
– Induction TPF àRT is better than PF àRT (NOT CCRT)
• CR rates
• LFS
• OS

Summary
v Treatment following CRT in LA HNC
– CR: follow up (?or elective surgery)
– Stabilization or progression: as metastatic
disease
– PR (residual)
• Surgery feasible
– R0: follow-up
– R1: ? as metastatic disease
• Surgery not feasible: ? as metastatic disease

Summary
v Very locally-advanced HNC
– Include T4b, unresectable N, unfit for surgery
– PS 0-1:
• CRT or ICTà RT/CRT
• ± surgery to T and or N if feasible
– PS 2:
• RT or CRT
– PS 3:
• Palliative RT
• Single agent chemotherapy
– PS 4:
• BSC

Summary
v Stage IV C (metastatic HNC)
– Options
• BSC
• Chemotherapy (single or combinations)
• Targeted therapy (MCAb or EGFR TKI)
• Chemo-targeted therapy
– Chemotherapy increases OS by ~ 2 M vs. BSC

Summary
v Chemotherapy in stage IV C (M1 HNC)
– Single agents and combinations yield similar OS (6-9
M)
– Taxanes produce higher RR (30%) than Mtx (15%) or
cisplatin (20%)
– Combinations yield higher RR and also toxicity than
single agents. Triplets are very toxic
– Platinum-taxane similar to platinum- NON-taxane
– Combination in young patients with good PS and
more symptoms
– PF or CF combination is acceptable

Summary
v Targeted therapy in M1 HNC
– Second-line
• Cetuximab (mcAB) produces ~ 13% RR and 5-6 M OS
• Afatinib (EGFR TKI) produces ~20% RR
– First-line (in combination with chemotherapy)
• Cetuximab + cisplatin: no OS advantage
• Cetuximab + PF (new standard) :
– Increase RR: 20%à33%
– Increase PFS: 3.3 m à5.6 m
– Increase OS: 7.1 m à10.4 m
– Increased toxicity

Treatment of M1 HNC
v PS 0-1:
– Combination chemotherapy (PF) + cetuximab
– Combination chemotherapy: PF or TP
– Single agent: MTX, docetaxel or others
– Surgery or RT in very selected cases
v PS 2:
– Single agent CTX
v PS 3-4:
– BSC

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