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Systemic therapy in head and neck cancers 2014 1
 

Systemic therapy in head and neck cancers 2014 1

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Review of the treatment of head and neck cancers

Review of the treatment of head and neck cancers
Head and neck cancer workshop: National Cancer Institute

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    Systemic therapy in head and neck cancers 2014 1 Systemic therapy in head and neck cancers 2014 1 Presentation Transcript

    • 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. Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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] Prof Ahmed Zeeneldin 2014
    • 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] Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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) Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof 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 Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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% Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • Comparisons of single agents 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. Prof Ahmed Zeeneldin 2014
    • Comparisons of single agents 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. Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • Single agent vs. platinum doublets Prof Ahmed Zeeneldin 2014
    • Single agent vs. platinum doublets • Combination: – Higher RR – Similar OS – Cisplatin better than carboplatin Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • Three-drug taxane-platinum combinations 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 Prof Ahmed Zeeneldin 2014
    • Three-drug taxane-platinum combinations 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. 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 Prof Ahmed Zeeneldin 2014
    • Targeted therapies • Classes: – mAB : cetuximab (not panitiumumab) – EGFR TKI: Affatinib • Use: – Single – In combination with chemotherapy Prof Ahmed Zeeneldin 2014
    • 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) Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • Treatment modalities in LA HNC • RT • Induction chemotherapy (IC) + RT • Concurrent Chemo-RT (CCRT) • Sequential TX (IC + CCRT) Prof Ahmed Zeeneldin 2014
    • 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). Prof Ahmed Zeeneldin 2014
    • RT vs. CCRT in unresectable LA HNC 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. Prof Ahmed Zeeneldin 2014
    • RT vs. CCRT in unresectable LA HNC 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 Prof Ahmed Zeeneldin 2014
    • 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. Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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. 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 : 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 Prof Ahmed Zeeneldin 2014
    • 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 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof 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: Prof Ahmed Zeeneldin 2014
    • 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
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • 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 Prof Ahmed Zeeneldin 2014
    • MACH-NC, 2009 update prognostic factors CCRT not to be used in • Stage I, II • PS >1 • Older Age • Site?? Prof Ahmed Zeeneldin 2014
    • MACH-NC, 2011 update Site analysis • OS is better in all sites with CCRT only Prof Ahmed Zeeneldin 2014
    • MACH-NC, 2011 update Site analysis • PFS is better in all sites with CCRT Prof Ahmed Zeeneldin 2014
    • 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) 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) 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 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/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) Once/twice-daily RT (D1–5) 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 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/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) 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-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 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
    • 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) Cisplatin (75 mg/m2, D1) 5-FU (750 mg/m2, D1–5, C1) q3wks, 3 cycles n = 110 Cisplatin (100 mg/m2, D1) 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
    • Pointreau et al, 2009. 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 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 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 • ± surgery to T and or N if feasible – PS 3: • Palliative RT • Single agent chemotherapy • ± surgery to T and or N if feasible – 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