Head and Neck cancer

Transcription

1 Head and Neck cancer Medical Oncologist s Role in Multidisciplinary Teams - Focus on Adjuvant & Neo-adjuvant Therapy - Hye Ryun Kim, M.D. Yonsei Cancer Center, Medical Oncology

2 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Summary

3 Anatomy Oral cavity: 44% Pharynx: 25% Larynx: 31% From: Cancer Management: A Multidisciplinary Approach

4 Multidisciplinary Team Approach Symptom palliation Keep voice Swallowing function HN Surgeon Medical Oncologist Better cosmesis Maintain mental health Social function Radiation Oncologist Dietician Rehab. Med.

5 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Summary

6 CASE I: Q1, Q2 44세 여자 1년 전부터 있던 Lt. tongue ulceration pathology (biopsy of tongue) squamous cell carcinoma s/p Lt. partial glossectomy with MRND & Reconstruction ( )

7 병리결과보고서 1) Histology type : Tongue, Lt. SCCa, MD, 2) Size: 3.7x3.4cm, invades intrinsic muscle, invasion depth 1.6cm 3) Lymph nodes: level IA (0/3), level IB (1/4), level IIA (4/11), level IIB (1/2), level III (1/8), level IV (0/12), level VA (0/6) and level VB (0/11); total (7/57) perinodal soft tissue extension (2/7) (maximal diameter: 1.7cm) - LVI (-), PNI(+) 4) Resection margins: negative stage IVa pt2n2bm0

8 Q1. 이환자에게시행해야하는 postop adjuvant therapy 에대하여 옳은것을고르시오. 1) Adjuvant chemotherapy 2) Adjuvant radiotherapy 3) Adjuvant chemotherapy sequential RTx 4) Adjuvant chemoradiotherapy (CCRTx) 5) Observation

9 Q2. 수술후보조항암방사선요법을시행시병합요법으로가장적절 한항암제를고르시오 1) Cisplatin 2) Cetuximab 3) Taxane 4) Taxol+ carboplatin 5) Cetuximab + Cisplatin

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11 EORTC Trial: Schema Surgery (oral cavity, oropharynx, hypopharynx, larynx) -pt3 or pt4 -N2 or N3 -pt1/t2 and N0/N1 with unfavorable patholgic findings Oral cavity ~30% Randomize 231 Pts RT Gy/30-33 Fr 228 Pts RT Gy/30-33 Fr Cisplatin 100 mg/m2, d1,22,43 Primary end point: Locoregional control Secondary end points: Disease-free survival, Overall survival, Adverse effects Unfavorable features: Extranodal spread, RM +, perineural involvement, vascular tumor embolism, oral cavity or oropharyngeal tumor with LN level IV or V

12 5-yr PFS 47% vs. 36% 5-yr OS 53% vs. 40%

13 Phase III Randomized Trials: Concurrent Chemo-RT vs. Radiotherapy alone EORTC (n = 334) RTOG 9501 (n = 410 ) Treatment DDP/RT (%) RT (%) P value DDP/RT (%) RT (%) P value 5 Y-LRF Y-DFS or PFS Y-OS Acute toxicity Gr < LRF, locoregional failure; DFS, disease-free survival; PFS, progression-free survival; OS, overall survival. Bernier J. N Engl J Med 2004;350: ; Cooper J. N Engl J Med. 2004

14 Conclusion: Postoperative Therapy Adjuvant concurrent chemoradiation in high-risk disease is standard of care ( MUST ) Addition of chemotherapy resulted in a significant increase in local control and DFS, OS (in EORTC) Cisplatin-based CRT is the current standard (100 mg/m 2 3-weekly or 30~40 mg/m 2 weekly)

15 Q1 이환자에게시행해야하는보조치료? 1) Adjuvant chemotherapy 2) Adjuvant radiotherapy 3) Adjuvant chemotherapy sequential RTx 4) Adjuvant chemoradiotherapy (CCRTx) 5) Observation

16 Q2 수술후보조항암방사선요법을시행시병합요법으로 가장적절한항암제를고르시오 1) Cisplatin 2) Cetuximab 3) Taxane 4) Taxol+ carboplatin 5) Cetuximab + Cisplatin

17 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Summary

18 NCCN Practice Guideline Risk features: extracapsular nodal spread, positive margins, pt3 or pt4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.

19 Role of Chemoradiation in LA-HNSCC Improved tumor control and OS in HNSCC, compared with RT alone MACH-NC: The biggest 5-yr absolute benefit 5.6% & pronounced effect on locoregional control Preferred option for organ preservation Toxicity, both acute and late, is enhanced Pignon JP, et al. Radiotherapy and Oncol, 2009 Trotti A et al. Radiother Oncol 2003

20 CRT is Better than XRT alone for Oropharynx Cancer: 5-year results Denis, F et al. JCO. 2004

21 Organ Preservation Protocol Achieve Similar Locoregional & Overall Control Rate Compared to Surgery Soo KC et al. Br J Cancer 2005

22 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Summary

23 Differential Effect on Failure Patterns CRT and Induction chemotherapy may be complementary Significant improvement in locoregional (LRC) and distant control (DC) with concomitant chemotherapy LRC: HR 0.74 ( ; p<0.0001) DC: HR 0.88 ( ; p=0.04) No improvement in LRC, but significant improvement in DC with induction chemotherapy LRC: HR 1.03 ( ; p=0.43) DC: HR 0.73 ( ; p=0.001) Induction chemotherapy has a more pronounced impact on distant control than concomitant chemotherapy Pignon JP, et al. Radiotherapy and Oncol, 2009

24 Do Induction Chemotherapy and CRT have Complementary Effects on Overall Control of Disease? A sequential approach Induction chemotherapy Definitive local therapy (RT or CRT) Active induction CT improves distant control & further improves locoregional control Brief dose-dense regimen without compromizing CCRT Avoiding a long delay of CCRT (selective repopulation of resistant tumor) Intensive local therapy regimen improves locoregional control

25 TAX324 (US) TPF vs PF Followed by Chemoradiotherapy R A N D O M I Z E T P F P F Carboplatin - AUC 1.5 Weekly EUA Surgery Daily Radiotherapy TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Posner, NEJM, 2007

26 TAX324: Patients Characteristics TPF (N=255) PF (N=246) Age (years): Median (Range) 65 years 55 (38 to 82) 34 (13%) 56 (33 to 80) 36 (15%) Gender Male 215 (84%) 204 (83%) PS (WHO) 0 1 Anatomic site Oropharynx Larynx Hypopharynx Oral cavity Clinical Stage III IV Reason Inoperability Technical Unresectability Low Surgical Curability Organ Preservation 142 (56%) 113 (44%) 132 (52%) 48 (19%) 42 (17%) 33 (13%) 41 (16%) 214 (84%) 92 (36%) 78 (31%) 85 (33%) 126 (51%) 117 (48%) 131 (53%) 42 (17%) 34 (14%) 38 (15%) 46 (18%) 199 (81%) 84 (34%) 75 (31%) 87 (35%)

27 TAX324: Overall Survival 100 Survival Probability (%) TPF 67% PF 54% 30% reduction in risk of death TPF 62% PF 48% TPF (n=255) PF (n=246) Log-Rank P = Hazard Ratio = Survival Time (months) Number of patients at risk TPF: PF:

28 TPF versus PF: Organ Preservation TAX324 subgroup: Operable laryngeal/ hypopharyngeral cancer GORTEC phase III 3-yr LFS: 52% (TPF) vs. 32% (PF) 3-yr LP: 70.3% (TPF) vs. 57.5% (PF) P= 0.03 Posner MR. Ann Oncol 2009; Pointreau Y. JNCI 2009

29 Summary of Induction Chemotherapy in Four Pivotal Trials Study, population TAX323, Inoperable TAX324, locally advanced GORTEC , resectable larynx/hypopharynx Spanish Head and Neck group, locally advanced N Primary endpoint Regimen Significant outcomes 358 PFS PF/RT vs. TPF/RT TPF better in PFS and OS, P < OS PF/CRT vs. TPF better in 5-year TPF/CRT PFS and OS, P= 0.01; 213 Larynx preservation 382 Overall CR rate PF/RT vs. TPF/RT PF/Paclitaxel/CRT vs. PF/CRT in LFS, P < 0.03 TPF better in LP, P < 0.04 PF/Paclitaxel better in CR rate (33% vs. 4%), P <0.001; in OS (43 mo vs. 37 mo), P= 0.03 Abbreviation: PF, cisplatin/5-fu; TPF, docetaxel/cisplatin/5-fu; CRT, concurrent chemoradiotherapy; LP, larynx preservation Posner MR, N Engl J Med 2007; 357: ; Vermorken JB, N Engl J Med 2007; 357: ; Pointreau Y, J Natl Cancer Inst 2009; 101: ; Hitt R, J Clin Oncol 2005; 23:

30 Induction Chemotherapy in LA-HNSCC TAX323/324 demonstrate TPF ICT superior to PF ICT in LA-HNSCC 3-yr OS ~10% Risk of death ~30% (HR ) (vs. CRT > PF induction, Δ 3.5%) 7~19% Complete response 10-20% LP or LFS

31 Important Questions Raised after TAX Studies Is induction chemotherapy followed by definitive local therapy superior to CRT alone? Dose induction chemotherapy decrease distant metastasis, thereby improve OS? (N2/N3)

32 Sequential Therapy vs Concurrent Chemoradiation only Group Regimen Boston (US) (Paradigm) Chicago (US) (DeCIDE) TPF x 3 CRT (carboplatin) CRT (cisplatin) TPF x 2 THFX THFX

33 Results of recent induction study PRADIGM DeCIDE

34 Overall Conclusion DeCIDE/PARADIGM/TTCC Adding TPF to CRT in LA-HNSCC Did not improve survival Improved cumulative incidence of distant failure

35 Phase III randomized study of IC followed by CCRT compared with concurrent chemotherapy alone in patients with N2 or N3 disease (DeCIDE) All patients N2a or 2b N2c or N3 J Clin Oncol 32:

36 Sequential Therapy for HNSCC: Experimental Therapy Induction Chemotherapy (TPF-based) CRT or RT When and For Whom? Good PS; Large or low neck node (+); Oropharynx, hypopharynx, larynx primary

37 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Treatment in metastatic SCCHN IV. Summary

38 CASE 2: Q3 62세남자 8개월간의 odynophagia Karnofsky performance status: 100% Comorbidity: HTN Smoking Hx: current smoker 50pyrs Laryngoscope 소견 Ulcerative mass on posterior hypopharyngeal wall No involvement in both arytenoid and pyriform sinus vocal cord intact Pathologic diagnosis: squamous cell carcinoma

39 Baseline image PET CT scan 31th Jan, 2013 MRI scan 31th Jan, 2013 Hypopharynx, posterior wall, SCCa, ct4a/bn2bm0, stage IVA T= Mass infiltrates hyoid bone, Possible invasion of prevertebral fascia. N= Metastatic LNs in both neck level II-III. (1.5cm)

40 Q3. 이환자에게시행할가장적합한치료방법은? 1) Operation 2) Operation post op adjuvant radiotherapy 3) definitive concurrent chemoradiotherapy 4) Induction chemo operation 5) Chemotherapy

41 Multiple molecular target in HNSCC EGFR pathway VEGF pathway Hypoxia C-MET IGF-1R pathway Downstream target of RTK (PI3K)

42 Erbitux + RT in locally advanced SCCHN: Phase III study design Oral cavity cancer excluded Stage III and IV non-metastatic SCCHN (n=424) Stratified by KPS Nodal involvement Tumor stage RT regimen R RT (n=213) Erbitux + RT (n=211) Erbitux initial dose (400 mg/m 2 ) 1 week before RT Erbitux (250 mg/m 2 ) + RT (weeks 2 8) 3-year locoregional control rate: 47% vs 34%, p< year overall survival rate: 55% vs 45%, p= year overall survival rate: 46% vs 36%, p=0.02 Bonner J, et al. N Engl J Med 2006;354: *Bonner J, et al. as presented ASTRO 2008

43 ERBITUX + RT: OS 5 year update ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years Probability of Overall Survival HR=0.73 ( ) p = 0.02 ERBITUX + RT Months Treatment Total Death Alive Median ERBITUX + RT RT RT p- value 5-year OS rate 46% 36% 0.02 Erbitux + RT RT Bonner J.A, et al. as presented ASTRO 2008

44 Erbitux + RT in LA SCCHN: - Indirect comparison with CRT - HR (95%CI) for Erbitux + RT relative to CRT Overall Survival 0.92 ( ) ( ) ( ) ( ) 4 Locoregional Control 1.15 ( ) ( ) ( ) Favors Erbitux + RT Favors CRT 1: Pignon et al. meta-analysis 2: All original studies with p-value 0.10 assumed for Forastière et al. (modified from Levy et al to correct an error in the publication) 3: All original studies with p-value 0.99 assumed for Forastière et al. 4: Only studies with comparable mortality to Bonner et al. in RT arm 5: All original studies reporting locoregional control as an outcome 6: Only studies with comparable mortality to Bonner et al. in RT arm 7: As for Locoregional Control 2, with adjusted hazard ratio used in place of unadjusted for Huguenin et al. Survival benefit of adding Erbitux to RT is within the same range as CRT. Levy AR, et al. Curr Med Res Opin 2011;27:

45 PET CT scan 31th Jan, 2013 MRI scan 31th Jan, 2013 PET CT scan 13 th May, 2013 Erbitux based CCRTx

46 Q3 이환자에게시행할가장적합한치료방법은? 1) Operation 2) definitive CCRTx 3) Induction chemo CCRTx 4) Induction chemo op 5) definitive Erbitux based RTx (ERT)

47 Optimizing quality of survival for patients with locally advanced SCCHN Adding Erbitux to RT significantly: Extends survival Prolongs disease control Increases response rate while maintaining the quality of that survival Erbitux + RT is appropriate for patients eligible f or CT Maximizing QoS is the principle of treatment of L ASCCHN

48 Contents I. Introduction II. Treatment in Locally advanced SCCHN - Upfront surgery + postop RT/CRT - RT-based treatment Concurrent chemoradiotherapy (CRT) Induction CTx CRT - CRT + cetuximab III. Summary

49 HPV in oropharyngeal ca Risk group based on HPV, tobacco use & T/N status - Possible role for dose de-escalation in patient subgroup- Ang KK et al New Engl J Med 2010;363:24-35

50 OS by HPV status in prospective trials

51 De-intensification candidate in HPV+ OPC HPV+ OPC 3yr Distant control rate (%) RT alone vs. CRT No significant differences Low risk group: T1-3N0-2a Good risk HPV+ tumors may do well with RT alone O Sullivan B et al J Clin Oncol 2013;31:543-50

52 Q4. LA-HNSCC 에관련한설명중틀린것을고르시오. 1) HPV + oropharynx cancer 환자는 HPV 환자보다예후가좋다. 2) Erbitux based concurrent chemoradiotherapy (CCRTx) 는 cisplatin based CCRTx보다생존율을증가시킨다. 3) Erbitux based CCRTx는 cisplatin based CCRTx에비하여삶의질측면에서우월하다. 4) Induction chemotherapy 은 LA-HNSCC 환자의생존율을증가시키지못하였다. 5) Unresectable 두경부암환자에대하여 induction chemotherapy를시행하여수술하는것은 standard care 가아니다.

53 Q4. LA-HNSCC 에관련한설명중틀린것을고르시오. 1) HPV + oropharynx cancer 환자는 HPV 환자보다예후가좋다. 2) Erbitux based concurrent chemoradiotherapy (CCRTx) 는 cisplatin based CCRTx보다생존율을증가시킨다. 3) Erbitux based CCRTx는 cisplatin based CCRTx에비하여삶의질측면에서우월하다. 4) Induction chemotherapy 은 LA-HNSCC 환자의생존율을증가시키지못하였다. 5) Unresectable 두경부암환자에대하여 induction chemotherapy를시행하여수술하는것은 standard care 가아니다.

54 Summary Adjuvant concurrent chemoradiation in high-risk disease is standard of care. Chemoradiation in LA-HNSCC is standard of care and improve tumor control and OS in HNSCC, compared with RT alone. Adding induction chemotherapy to CRT in LA-HNSCC did not improve survival. Consider in subset group: Good PS; Large or low neck node (+); Oropharynx, hypopharynx, larynx primary. Erbitux based CRT is comparable in survival outcome and better in QoL compare with CRT.

55 This small recurrent disease will eventually kill our patient Scar from previous surgery Dermatitis from previous RT

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