State of the art for radiotherapy of SCCHN

Transcription

1 State of the art for radiotherapy of SCCHN

2 Less side effects Cured More organ & function preservation Head & neck cancer = new cases / year in Europe Not cured Local failure Distant failure More effective systemic treatment

3 Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

4 Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

5 The more intense RT-CT, the better? Phase 3 randomised GORTEC trial Randomized trials EBM level 1 MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Other randomized trials

6 Lessons from randomized trials : 70 Gy / 7 weeks alone = Perhaps the worst we can do! Adaptive RT RT-CT + X%? Altered fractionation Induction CT Cetuximab + RT + 13% + 10% + X%? + 10%

7 Lessons from randomized trial (II) Level of Evidence (EBM-1) Altered Fractionation Chemo-RT Hypoxia targeting Other EGFr targeting Cetuximab Induction Chemo IMRT Use in routine practice

8 Lessons from randomized trial (II) Level of Evidence (EBM-1) Altered Fractionation Chemo-RT Hypoxia targeting Other EGFr targeting Cetuximab Induction Chemo IMRT Use in routine practice

9 Concomitant chemo-rt More efficient on tumor control / survival But also more side effects ++! = is considered in Europe as a standard of care

10 MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Risk of recurrence (%) Why CT-RT is a standard treatment? Chemotherapy Control Local failure 63.2 % 49.7 % Distant failure 18.9 % 16 % RT Concominant RT + 5FU-platin Time from randomisation (Years) Pignon et al Radiother Oncol 2009

11 Which type of concomitant CT-RT? Which drugs? Increasing / decreasing the dose intensity?

12 MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Type of hemotherapy Survival by type of concomitant CT No. Deaths / No. Entered LRT+CT LRT O-E Variance Hazard Ratio HR [95% CI] p of interaction (a) Poly chemotherapy 5-FU and Platin 602 / / [0.67;0.84] p = FU or Platin 495 / / [0.74;0.94] Neither 5-FU nor Platin 62 / / [0.52;1.01] Subtotal (a) 1159 / / [0.72;0.85] (b) Mono chemotherapy Mono cisplatin 703 / / Mono Other 1309 / / Subtotal (b) 2012 / / [0.67;0.82] 0.89 [0.82;0.96] 0.84 [0.78;0.89] p = Total (a b) 3171 / / [0.78;0.86] Test for heterogeneity: 2 1 = 1.69 p = LRT+CT better LRT better

13 Which type of concomitant CT-RT? (I) Which drugs? Decreasing the dose intensity of Chemo?

14 A randomized trial (USA, 1987) included in the MACH-NC database Concomitant 20 mg / m2 / week : no benefit 1.0 OS ; p=0.81 Probability of survival Cisplatin 20mg/m 2 qw + RT (n=149) RT alone (n=159) Time (years)

15 Gortec trial, 2 versus 3 cycles (257 patients who received at least 68 Gy) chemo cycles chemo cycles 3 chemo cycles chemo cycles 0.80 At risk cycles 2 cycles Years At risk 3 cycles 2 cycles Years PFS Survival HR = 1.44 ( ) HR = 1.40 ( ) p = 0.05 p = 0.07 Bourhis et al Lancet Oncol 2012

16 Gortec trial, 2 versus 3 cycles (patients who received at least 68 Gy) chemo cycles chemo cycles 3 chemo cycles chemo cycles cycles cycles cycles cycles At risk Years At risk Years Locoregional failures HR = 1.52 ( ) p = 0.09 Distant metastases HR = 1.82 ( ) p = 0.05 Bourhis et al Lancet Oncol 2012

17 Which type of concomitant CT-RT? (I) Which drugs? Increasing the dose intensity of RT?

18 CT-RT +..? Adaptive RT RT-CT Altered fractionation Induction CT Cetuximab + RT + 13% + 10%?

19 CT-RT : No gain by increasing the dose intensity of RT Probability of loco-regional progression Patients at risk Very accelerated RT alone Accelerated RT + 2 cycles CT Conventional RT + 3 cycles CT Years Bourhis J, et al. Lancet Oncol 2012.

20 Which type of concomitant CT-RT? (I) Which drugs? Decreasing the dose of RT?

21 Small variations in dose major impact 70 Gy + Cisplatin, N= 840 patients randomized 100 Estimated percentage locoregional failure-free (Peters JCO 2010) P < compliant plan by TMC no adv impact adv impact Years following end of radiotherapy < 10% PTV Less than 66.5 Gy > 10% of PTV Less than 66.5 Gy

22 No compromize with the dose of RT +++ but can we decrease safely the volume of RT? to decrease side effects?

23 Evolution of SCCHN radiotherapy 2-D 3-D IMRT / 4D < 1950

24 GTV 70 Gy = 44 cc

25 High risk 70 Gy (+ 5 mm) = 93 cc

26 Elective 50 Gy = 879 cc Tomotherapy)

27 50Gy 3D conformal RT = 1489 cc

28 Gain with IMRT Nutting et al, Lancet Oncol 2011 The PARSPORT trial

29 Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

30 Beyond Parotid sparing : parotid stem cells sparing? Region of major salivary ducts most radiosensitive part stem cells located along salivary ducts (mouse, rat, humans) C-kit positive cells Van Luijk, et al. ESTRO 2012

31 Stem-cell sparing IMRT Planning comparison study Based on planning comparison: expected reduction severe xerostomia (<25% salivary at baseline): 50% <20% Van Luijk, et al. ESTRO 2012

32 Ongoing randomized trial (Groningen, Netherland) N = 102 HNC patients randomized Stem-cell sparing IMRT Standard whole parotid sparing IMRT

33 Prevention of Dysphagia RT Dose to the pharyngeal constrictor muscles (PCM) = variable for tube feeding dependence DOSE VOLUME PARAMETERS OTHER FACTORS Sex Age Tumour-stage Nodal-stage RT technique Chemotherapy Fractionation Site Baseline dysphagia Weight loss Christianen, et al. Radiother Oncol 2012

34 Swallowing sparing IMRT Translation from DOSE reduction to RISK reduction NTCP (%) 70% 60% 50% 40% 30% Dmean supraglottic = 10 Gy Dmean supraglottic = 20 Gy Dmean supraglottic = 30 Gy Dmean supraglottic = 40 Gy Dmean supraglottic = 50 Gy Dmean supraglottic = 60 Gy Dmean supraglottic = 70 Gy St-IMRT SW-IMRT 20% 10% 0% Mean dose PCM superius Van der Laan, et al. Radiother Oncol 2011

35 Carotid sparing IMRT : example in early glottic cancer Bilateral carotid dose V35 (ml) Mean, SD Range Median V50 (ml) Mean, SD V63 (ml) Mean, SD 0.45, , , 0.0 N = 23 patients treated at CHUV Median Follow-up = 4 years, Local control = 100%

36 Uni or bilateral radiotherapy? - Well (very) lateralized tumors - Minimal nodal involvement - Other than base of tongue & soft palate tumors

37 The future : Adaptive RT with molecular imaging 2-D 3-D IMRT / 4D Dose Painting Molecular imaging 2010 > < 1950

38 Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

39 De-escalation for HPV? Molecular targeted agents What else Can be Optimized? Induction CT? Immunotherapy

40 De-escalation for HPV? Molecular targeted agents What else Can we Optimize? Induction CT? Immunotherapy

41 ECOG 1308 : HPV+ specific randomized trial

42 RTOG Cetuximab-RT vs. CT-RT if HPV(+) Eligibility OPC P16 (+) Stage III / IV R A N D O M IZ E RT 70 Gy/35f/6 wks + cisplatin x 2 RT 70 Gy/35f/6 wks + cetuximab for 8 wks

43 De-escalation for HPV? Molecular targeted agents What else Can be Optimized? Induction CT? Immunotherapy

44 New insights for induction? Phase III randomized study TPF* cetuximab + RT vs carboplatin + 5-FU + RT Progression-free survival (%) PFS (primary endpoint) TPF * cet + RT CRT T2 4, N2b c N3 LA SCCHN At risk: Time since random assignment (years) CRT TPF cet + RT ; 2. Geoffrois L, et al. ASCO 2016 (Abstract No. 6000)

45 TPF related mortility in randomized trials TPF related Mortality (%) % %

46 TPF related mortility in randomized trials TPF related Mortality (%) Larynx preservation Nasopharynx Larynx preservation Locally advanced Locally advanced N2-N3

47 TPF related mortility in randomized trials TPF related Mortality (%) Larynx preservation Locally advanced Locally advanced N2-N Larynx preservation Nasopharynx Co-morbidies

48 De-escalation for HPV? Molecular targeted agents What else Can we Optimize? Induction CT? Immunotherapy

49 Clinical trials of molecular targeted therapies in HNSCC EGFr targeting Vandetanib Zalutumumab Erolitinib Afatinib Lapatanib Gefitinib AMPK activator PDK inhibitor Nilotinib (c kit) MEK inhibitor Trametinib Panitumumab Nimotuzumab Approved Cetuximab Nimorazole Celecoxib COX2 inhib Phase I-II Phase III Tirapazamine MET/VEGFR inhibitor Foretinib MET, VEGFR-2 E7050/Golvatinib MET inhibitor LY ONYX-015 p53 Advexin p53 Pazopanib PI3K inhibitor PX866, BKM120, BYL719, Rigosertib Sunitinib Bevacizumab Sorafenib Axitinib AKT inhibitor MK2206 mtor inhibitor Rapamycin Everolimus Temsirolimus V-EGF inhibitors Others

50 Clinical trials of molecular targeted therapies in HNSCC Phase I-II EGFr targeting AMPK activator PDK inhibitor Nilotinib (c kit) Vandetanib Zalutumumab Erolitinib Afatinib Lapatanib Gefitinib Nimotuzumab MEK inhibitor Panitumumab Phase III Approved Cetuximab Pazopanib Sunitinib Bevacizumab Sorafenib Axitinib AKT inhibitor mtor inhibitor V-EGF inhibitors MET inhibitor PI3K inhibitor Others

51 Randomized Phase III trials testing EGFr targeting in HNSCC : cetuximab is the exception (and ---does not work with CT-RT RTOG ) Compound Mechanism of action outcome Gefitinib EGFR TKI negative Erlotinib EGFR TKI negative Afatinib EGFR/HER2 TKI Ongoing Cetuximab EGFR Chimeric MAb positive Panitumumab EGFR Humanized MAb negative Zalutumumab EGFR MAb negative Lapatinib EGFR/HER2 TKI negative The only EGFr targeting agent working (ADCC?)

52 CT-RT +..? Adaptive RT RT-CT Altered fractionation Induction CT Cetuximab + RT + 13% + 10%?

53 Adding cetuximab to CT-RT? RTOG H05-22 : Phase III (940 pts) R Stage III-IV A N D O M I Z RT + CDDP RT + CDDP + cetuximab The addition of cetuximab to RTcisplatin : - No benefit in PFS / OS. - More mucositis and skin reactions E

54 Adding chemotherapy to cetuximab-rt? GORTEC = Treatment intensification with a cetuximab backbone Bourhis J, et al. ASCO 2016 (Abstract No. 6003) * Off-label regimen for Erbitux

55 GORTEC Progression-free-survival No. at risk: CT-cetux-RT** 20 Cetux-RT Progression-free survival Years since randomization Median follow-up of 4.4 years (CT-cetux-RT), 4.6 years (cetux-rt) *HR adjusted for N (0 vs 1 2), T (0 2 vs 3 4) and center in Cox model HR* 0.73 ( ) 2-sided log-rank p= CT-Erbitux-RT** Erbitux-RT Primary endpoint met (PFS) PFS at 3 years (95% CI): CT-Erbitux-RT** 52.3% (45 59) Erbitux-RT 40.5% (34 48) 55 ** Off-label regimen for Erbitux Bourhis J, et al. ASCO 2016 (Abstract No. 6003)

56 Optimisation of RT-CT Locally Advanced HNSCC New molecular targeted agents New induction CT Combination with Immunotherapy

57 PD-1 inhibitors = the highest response rate of any single-agent immunotherapy, Activated T cell Inhibitors of PD-1 and PD-L1 prevent the tumour cell from binding to PD-1, enabling the T cell to remain active.

58 State of the art for radiotherapy of SCCHN - RT-CT : - RT-CT = a Standard of care - Importance of RT / CT dose and of RT-QA & IMRT - No need to increase the dose-intensity of RT - Beyond parotid sparing? - New approaches - Induction CT? - HPV / de-escalation? - New combinatory approaches with immunotherapy