Systemic therapy in head and neck cancers 2014 1

Systemic therapy in Head and neck cancers

Prof Ahmed ZeeneldinProf 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 cmM 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 groupingT1

2cmT2

4cmT3

>4 cmT4a

+invadeT4b

++ invadeM1

N0 I II III IVA IVB IVCN13cmSIPSI

III III III IVA IVB IVC

N23-6 cm

IVA IVA IVA IVA IVB IVC

N3>6cm

IVB IVB IVB IVB IVB IVC

Stage GroupingI:T1II:T2III:T3, N1

IV: T4, N1-2, M1IVA: T4A, N2IVB: T4B, N3IVC: M1


ClassificationT1

2cmT2

4cmT3

>4 cmT4a

+invadeT4b

++ invadeM1

N0 EARLY Locally advancedMetastatic

N13cmSIPSI

Locally advanced

N23-6 cm

N3>6cm

• Very advanced HNC:• T4b• unresectable N• unfit for surgery


Surgical resectabilityT1

2cmT2

4cmT3

>4 cmT4a

+invadeT4b

++ invadeM1

N0 I, IIEARLY

Resectable

III-IVBLocally advanced

IVCMetCTIII

??ResectableIVA??

IVBIrresectable

N13cmSIPSI

IIILocally advanced

Resectable

As above

N23-6 cm

IVALocally advanced

??? Resectable

N3>6cm

IVBLocally advanced

?? Irresectable


TreatmentT1

2cmT2

4cmT3

>4 cmT4a

+invadeT4b

++ invadeM1

N0 EARLYResectable

S=RT

Locally advanced IVCMetCT

ResectableCRT

??CRT

IrresectableCRT

N13cmSIPSI

Locally advancedResectable

S, CRT

As above

N23-6 cm

Locally advanced??? Resectable

CRT

N3>6cm

Locally advancedIrresectable

CRT


Treatment of Early HNCStage 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 HNCStage 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):283-289Prof Ahmed Zeeneldin 2014

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 CTAnalysis 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 22Dose 40-60 mg/m q W 50 mg/m d1,8 q4WRR 24% 29% 0.51Duration of response

84 days 92 days

Median OS 6.1 m 6.3 m NSToxicity Mucositis (40%) Vomiting (90%)

Cancer. 1983 Jul 15;52(2):206-10.



Mtx Cisplatin pNo 50 50RR 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.Prof Ahmed Zeeneldin 2014


Mtx Docetaxel pNo 20 37 (2:1

randomizationDose 40 mg/m/w 40 mg/m/wRR 15% 27%TTP Similar SimilarOS Similar Similar

Eur J Cancer. 2004 Sep;40(14):2071-6.


Single agent vs. platinum doublets

PF CF Mtx PDose (q3w) P:100mg/m d1

F: 1000mg/md1-4Cb:300mg/m d1F: 1000mg/md1-4

40 mg/m/w

RR 32% 21% 10% <0.05Response duration NSOverall survival 6.6 M 5.0 M 5.6 M NSToxicity 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 d1F: 1000 mg/m

d1-4

T:175 mg/m 3h d1P: 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 D1P: 40 mg/m d1, 2F: 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 d1Ifo + mesna: 1000 mg/m ICI d1-5P: 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 d1Ifo + mesna: 1000 mg/m 2h d1-3P: 60 mg/m d1

pacli: 175 mg/m d1Ifo + 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 rate1J Clin Oncol 2005; 23: 3562–3567

2Cancer 2001; 91: 1316–1323.Prof Ahmed Zeeneldin 2014

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 therapyCetuximab 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 therapyCetuximab + 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 therapyCetuximab + Cisplatin

DDP DDP-cetux p

No 60 57

Dose (q 4W)

P:100 mg/m D1

P: 100 mg/m D1Cet: 200 mg/m w1125mg/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.Prof Ahmed Zeeneldin 2014

Targeted therapyCetuximab + 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 d1Or carbo AUC 5 d1FU 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 therapyPanitumumab+ 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: allP16 negative

9 M8.6 M

11.1 M11.7 M

0.140.01

Cis: 100 mg/m d1FU 1000 mg/m d1-4+/- Panitumumab: 9 mg/ kg d1

Lancet Oncology, 2013: 14(8) 697 - 710,

SPECTRUM STUDY


Targeted therapyAfatinib 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 HNCAdjuvant after CCRT


TreatmentT1

2cmT2

4cmT3

>4 cmT4a

+invadeT4b

++ invadeM1

N0 Locally advanced

ResectableCRT>S

??CRTàS

IrresectableCRT

N13cmSIPSI

Locally advancedResectable

S, CRT

As above

N23-6 cm

Locally advanced??? Resectable

CRTàSN3>6cm

Locally advancedIrresectable

CRT


Treatment of locally advanced HNCStage 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/CRTCRTà±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 HNCIntergroup 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 vs. CCRT in unresectable LA HNCRT 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 HNCIntergroup 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 vs. CCRT in unresectable LA HNCRT 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 recommended


cisCCRT weekly (40mg/m) vs 3 weekly (100mg/m)

Tsan et al. Radiation Oncology 2012, 7:215 Prof 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 PFàRTin Resectable glottic or surpraglottic SCCHN

(organ preservation): RTOG 91-11 Trial

Forastiere et al, 2003, 2006.

Resectable Stage III/IV SCCHNv Glottic or supraglottic

cancerv 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)RANDOMIZE

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.Prof Ahmed Zeeneldin 2014

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 : SICT vs RT: NS

2y- LFS5-y LFS

53%*33.9%*

66%*46.6%*

59%44.6%

0.010.011

2-y DFS5-y DFS

44%27.3%

61%39%

52%38.6%

CCRT vs RT =0.006ICT vs RT = 0.02

2-y Local control5-y Local control

58%51%

80%68.8%

64%54.9%

CCRT vs RT & ICT: SICT vs RT: NS

2-y Distant metastases5-y Distant metastases

16%*22.3%

8%*13.2%

9%14.3%

0.030.06

2-y OS5-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.Prof Ahmed Zeeneldin 2014

RTOG = Radiation Therapy Oncology Group.Forastiere et al, 2006.

RTOG 91-11 Results: LFS and OS

Aliv

e (%

)0 1 2 3 4 5 6 7 8 9 10

LFS

Aliv

e W

ithou

t Lar

ynge

ctom

y (%

)

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 + inductionRT + concomitantRT 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 glotticor 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 analysisProf Ahmed Zeeneldin 2014

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 CancerInt. J. Radiation Oncology Biol. 2007 Phys.,69 (2):S112–S114

MACH-NC, 2007 update Effect of age

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

MACH-NC, 2009 update

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, Prof Ahmed Zeeneldin 2014

MACH-NC, 2009 update concomitant CTX agent


MACH-NC, 2009 update 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


MACH-NC, 2009 update 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


MACH-NC, 2009 update prognostic factors

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


MACH-NC, 2011 update Site analysis

• OS is better in all sites with CCRT onlyProf Ahmed Zeeneldin 2014

MACH-NC, 2011 update Site analysis

• PFS is better in all sites with CCRT


Phase III Trial of TPFàRT Vs. PFàRTTAX 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 UnresectableStage III/IV SCCHN

v Excluding nasopharynx, nasal, and paranasalcavities

v Uni- or bidimensionallymeasurable disease

vWHO PS 0/1v Adequate hematologic,

hepatic, and renal function

N = 358

RANDOMIZE

Docetaxel (75 mg/m2, D1)Cisplatin (75 mg/m2, D1)5-FU (750 mg/m2/d, D1–5, C1)q3wks, 4 cycles

Cisplatin (100 mg/m2, D1)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)orAccelerated/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 323PFS TPFàRT PFàRTMedian PFS 11.0 M 8.2 M

HR (95% CI) 0.72 (0.57–0.91)p Value .007

OS TPFàRT PFàRTMedian PFS 18.8 M 14.5 M5-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 SCCHNv Oral cavity,

oropharynx, hypopharynx, larynx

N = 501

RANDOMIZE

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 CRTDocetaxel (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 TPFn = 255 (95% CI)

PFn = 246 (95% CI) p Value

ORR (ICT) 72% (65.8–77.2) 64% (57.9–70.2) .07CR (ICT) 17% (12.1–21.6) 15% (10.8–20.1) .66ORR (ICT + CRT) 77% (70.8–81.5) 72% (65.5–77.1) .21CR (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 = .0058HR = 0.70

TPF 53%PF 42% TPF 49%

PF 37%

Log-rank p = .004HR = 0.701

Survival PFS

Time (mos)

Sur

viva

l Pro

babi

lity

(%)

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)

PFS

Pro

babi

lity

(%)

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: ToxicityGrade 3/4 Toxicity TPF (%) PF (%)Stomatitis 21 27Nausea 14 14Lethargy 5 10Vomiting 8 10Diarrhea 7 3Anorexia 12 12Neutropenia 84 56Febrile Neutropenia 12 7Neutropenic Infection 12 9Stomatitis 37 38Dysphagia 23 24Mouth, Nose Dryness 5 4Nausea 6 6Rash/Itch 5 2

During ICTN = 251 TPF,243 PF

During CRTN = 203 TPF,184 PF


oropharynx, hypopharynx,

vNOT larynx

N = 101

RANDOMIZE

Same CRT

Docetaxel (75 mg/m2)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/CRTn = 50

PF/CRTn = 51 p Value

CR TPF 6.5%CR CRT 50% 21.3% 0.004Surgery for rad/clinical residual 19.5% 38.2% 0.047

Cis 20 mg/m/d d1-4FU 800mg/m/d d1-4 W1 & W6 of Daily RT (5 d/wk 70 GY)

TPF/ICTàPF/CRT vs. PF/CRT

vDespite 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.

ParadigmStage III/IV SCCHNv Oral cavity,

oropharynx, hypopharynx, larynx

Expected N = 330

RANDOMIZE

DocetaxelCisplatin5-FUq3wks, 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)Once/twice-daily RT (D1–5)6 wks

CR

PR

ICT CRT

v Primary end point: 3-yr survivalv 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


oropharynx, hypopharynx,

v larynx

N = 145

RANDOMIZE

Docetaxel (75 mg/m2)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/CRTParadigm trial

Radiologic Response TPF—CRTn = 70

Cis/CRTn = 75 p Value

3-y OS rate 73% 78% 0.773-y PFS 67% 73% 0.55

RT: Daily RT (5 d/wk 70 GY)Cis 100mg/m/d d1-29

RT with either Carboplatin weeklyDocetaxel weekly

Clin. Oncol. 28(Suppl. 15), Abstract 5563 (2010).

Phase III TPFàCRT vs. CRTNorth America: DeCIDE

DeCIDEChemotherapy and RT-Naïve SCCHNN2/N3 disease

Expected N = 400

RANDOMIZE

v Primary end point: OS

v Secondary end points: Distant FFS, failure pattern, PFS, QOL

ICT-CRT CRT P valueDistant Mets 10% 19% 0.0253-y OS 75% 73% 0.7

(Abstract 550). 2012 ASCO Annual Meeting. (2012).

DocetaxelCisplatin5-FUq3wks, 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)Once/twice-daily RT (D1–5)6 wks

ICT CRT

Phase III Trial of PCFàcisCRT Vs. CFàcisCRT

Treatment-NaïveStage III/IV SCCHN

v Excluding nasopharynx, nasal, and paranasalcavities

v Uni- or bidimensionallymeasurable disease

vWHO PS 0/1v Adequate hematologic,

hepatic, and renal function

N = 358

RANDOMIZE

Paclitaxel (175 mg/m2, D1)Cisplatin (100mg/m2, D1)5-FU (500mg/m2/d, D2–6, C1)q3wks, 3 cycles

Cisplatin (100 mg/m2, D1)5-FU (1,000 mg/m2/d,D1–5, C1)q3wks, 3 cycles

Conventional daily RT (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).

Conventional daily RT (2.0 Gy/d, 5 d/wk, total 70 Gy)

Cisplatin 100 mg/m D1, 22, 43


Response (ICT + RT)

CFàcisCRT(n = 193)

PCFàcisCRT(n = 189) p Value

CR (ICT) 14% 33% <.001CR (ICT + CRT) 78% 88% NSTime to TX failure 12 M 20 M 0.006Median OS 37 M 43 M 0.06Median OS (unresectable) 26 M 36 M 0.04

Mucositis >G1 53% 16%

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 HypopharynxCancerRequiring total laryngectomy

N = 220

RANDOMIZE

Docetaxel (75 mg/m2, D1)Cisplatin (75 mg/m2, D1)5-FU (750 mg/m2, D1–5, C1)q3wks, 3 cyclesn = 110

Cisplatin (100 mg/m2, D1)5-FU (1,000 mg/m2, D1–5, C1)q3wks, 3 cyclesn = 103

ICT

SurgeryPostop 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

Pointreau et al, 2009.

p = .11

DFS

p = .57

OS

p = .03

LP

GORTEC 2000-01: Results

Outcome at 3 Yrs TPF (%) PF (%) p ValueLarynx Preservation rate 70.3 57.5 .03

DFS 58 44 .11OS 80 60 .57

GORTEC 2000-01: Response and Toxicity

Selected Acute Toxicities TPF (%) PF (%)Alopecia (grade 2) 19 2Stomatitis (grade 3/4) 4.6 7.8Neutropenia (grade 4) 31.5 17.6Febrile Neutropenia (grade 3) 10.9 5.8Thrombocytopenia (grade 3/4) 1.8 7.8Creatinine (grade 4) 0.0 2.0

TPF (%) PF (%) pLP rate 70.3 57.5 .03CR 41.8 30.1 NRPR 38.2 29.1 NRCR + PR 80.0 59.2 .002

Pointreau et al, 2009.

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

vCetuximab

vPanitumumab

v TKI afatinib?

Phase III Study of Cetuximab + RT for Locoregionally Advanced SCCHN

N = 424v Locoregionally

advanced SCCHN

v Treatment naivev KPS 60%–

100%

Cetuximab, 400 mg/m2, Wk 1 + 250 mg/m2 qwk, Wks 2–8 + RT, Wks 2–8a

n = 211

RTa Alonen = 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.

RANDOMIZE

End pointsv Duration of disease controlvOS, 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

Loco

regi

onal

Con

trol (

%)

RT

0 10 20 30 40 50 60 70

Cetuximab w/RT

RT Alone

HRa

(95% CI) p ValueDuration of control(mos)

24.4 14.90.68

(0.52–0.89)

.005

Cetuximab + RT in Locoregionally Advanced SCCHN: OS

Bonner et al, 2006a, 2006b, 2010.

100

80

60

40

20

00 10 20 30 40 50 60 70

RT

Time (mos)

RT + cetuximabOS

(%)

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 M0.74

(0.57–0.95).03

Cisplatin versus cetuximab plus concomitant RTin 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 + CETRisk ratio (95%

CI) P value

2-yr OS 71 % 60.7 % 0.66 (0.46-0.94) 0.022-yr DFS 61.7 % 43.1 % 0.68 (0.53-0.87) 0.0022-yr LRR 19.6% 32.3% 0.63 (0.45-0.87) 0.005Distant Mets Same Same 1.01 (0.69-1.48) 0.94

J Clin Oncol 32:5s, 2014 (suppl; abstr 6014)

vChemoradiation is the standard of care for locally advanced SCCHN.

vDefinitive 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 cetuximabconstitutes 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

Nasopharynxv 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 tumorsv 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 tumorsvunresectable T3, T4a AND T4b

– RT/CRT

vM1 disease– Ps 0-2:

• Chemotherapy

• Selected metastatectomy

• Expectant management in slowly growing tuomrs

– PS 3-4:• BSC

Summaryv 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,

Summaryv 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

Summaryv 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

vStage 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

vChemotherapy 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

vPS 0-1:– Combination chemotherapy (PF) + cetuximab

– Combination chemotherapy: PF or TP

– Single agent: MTX, docetaxel or others

– Surgery or RT in very selected cases

vPS 2:– Single agent CTX

vPS 3-4:– BSC

Systemic therapy in head and neck cancers 2014 1

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