Spanish trial Spanish trial CDDP 100 mg/m 2 R 5FU 1 g/m 2 A 382 N Stage III – IV D RT (70Gy) SCC CR or PR > 80% CDDP (100 mg/m 2 ) O Oral cavity M Oropharynx I Paclitaxel 175 mg/m 2 Hypopharynx Z CDDP 100 mg/m 2 E 5FU 500 mg/m 2 Hitt et al. JCO , 2005 Hitt et al. JCO , 2005
Spanish trial Spanish trial Median follow up: 2 years CR OS Mucositis 14% 193: CF 37 months 53% 33% 189: PCF 43 months 16% P < 0,001 P = 0,06 P = 0,06 Hitt et al. JCO , 2005 Hitt et al. JCO , 2005
Spanish trial Spanish trial Overall Survival for unresectable disease Overall Survival for unresectable disease PCF CF 36 m Vs 26 m; p =0,04 Hitt et al. JCO , 2005 Hitt et al. JCO , 2005
Spanish trial Spanish trial Hitt et al. JCO , 2005 Hitt et al. JCO , 2005
What is best timing and scheme of What is best timing and scheme of CT in Head & Neck cancer when CT in Head & Neck cancer when combined with RT or Surgery? combined with RT or Surgery?
Updated: Bourhis at ASCO 2004
The main Meta-analysis - Findings The main Meta-analysis - Findings � 63 trials – 10 741 patients � Comparison of loco-regional treatment with or without CT � Survival benefit of 4% at 2 and 5 years when CT was employed � No significant benefit with adjuvant or neoadjuvant CT � CT concomitantly with RT gave significant benefit Pignon et al. The Lancet , 2000 Pignon et al. The Lancet , 2000
The main Meta-analysis - Findings The main Meta-analysis - Findings Regimen Trials Patients RR P value 5y benefit Neoadjuvant 31 5269 0.95 NS 2% Adjuvant 8 1854 0.98 NS 1% Concurrent 26 3727 0.81 <0.0001 8% Pignon et al. The Lancet , 2000 Pignon et al. The Lancet , 2000
CT Control Courtesy of Jean Bourhis Courtesy of Jean Bourhis
MACH – NC update MACH – NC update 1. The magnitude of benefit with CT is higher for platin-based CT than for other CT drugs ( p <0.01) 2. No significant difference between concomitant mono-CT and concomitant poly-CT Bourhis et al. JCO , 2004 Bourhis et al. JCO , 2004
What is the best platin-based What is the best platin-based CT administration schedule CT administration schedule during concurrent RT? during concurrent RT? Daily? Weekly? Every 3 weeks? Daily? Weekly? Every 3 weeks?
Platin schedule administration Platin schedule administration � The main trials that have proven the benefit of concurrent CDDP with RT have used dose of 100 mg/m 2 every 3 weeks (Days 1,22,43) � Just one trial has showed benefit of daily CDDP (Jeremic et al., JCO 2000), but the logistic of this administration is uncomfortable for the patients � Two prospective and randomized trials that used weekly CDDP with RT were negative (Head and Neck INTERGROUP; Haselow et al., 2003 and NPC Korean Trial. Chan et al., 2005) � No benefit of weekly CDDP when compared with RT alone
Altered fractionated RT Altered fractionated RT
Altered fractionated RT Altered fractionated RT � The RTOG 90-03 trial showed that altered fractionated RT improves loco-regional control and disease-free survival, mainly with hyperfractionated (HFX) schedule, when compared to conventional fractionation (QD RT) Fu et al. Red J , 2000 Fu et al. Red J , 2000 � The French meta-analysis showed that altered fractionation increased 5-year LC by 6.7% and OS by 3.4%. The benefit was even better with HFX regimens (8% at 5 years) Bourhis et al. Lancet , 2006 Bourhis et al. Lancet , 2006
� Analysis of 15 trials � 6515 patients � Stages III – IV � Median FU: 6 years � Survival: HR=0.92 (95% CI: 0.86 – 0.47) p =0.03 Bourhis et al. Lancet , 2006 Bourhis et al. Lancet , 2006
HPX HPX All groups All groups Bourhis et al. Lancet , 2006 Bourhis et al. Lancet , 2006
What about altered What about altered fractionated RT + CT? fractionated RT + CT?
Altered fractionated RT + CT Altered fractionated RT + CT � The results of HPX is better than QD RT but is not better than concurrent CT and QD RT � Toxicity of altered fractionation RT is higher than QD RT � Can CT + HPX RT lead to further improvement of results with acceptable toxicity?
Duke Randomized Trial Duke Randomized Trial HFX + CT 70Gy 1.25 BID R A 2 x CDDP + 5FU N=122 N (Split course) Stage III – IV D Oropharynx O Hypopharynx M Oral cavity I NPC HFX Alone Z Sinus 75Gy 1.25 BID E Brizel et al. NEJM , 1998 Brizel et al. NEJM , 1998
Duke Randomized Trial Duke Randomized Trial Median follow up: 41 months Brizel et al. NEJM , 1998 Brizel et al. NEJM , 1998
Duke Randomized Trial Duke Randomized Trial 5y-LRC 5y-DFS 5y-OS Tox G III 42% RT + CT 70% 60% 77% 40% RT 44% 28% 75% P = 0.01 P = 0.08 P = 0.07 Hitt et al. Uptaded at ASTRO 2007 Hitt et al. Uptaded at ASTRO 2007
Switzerland Randomized Trial Switzerland Randomized Trial R HFX Alone A 74.4Gy 1.2 BID N=224 N Stage III – IV D SCC O M Oropharynx I HFX + CT Hypopharynx Z 74.4Gy 1.2 BID Larynx E 2 x CDDP (20mg/m 2 ) W1 and W5 Huguenin et al. JCO , 2004 Huguenin et al. JCO , 2004
Switzerland Randomized Trial Switzerland Randomized Trial 5y-LC 5y-LRC 5y-DMF 5y-OS RT + CT 64% 51% 61% 46% 33% RT 36% 40% 32% P = 0.01 P = 0.04 P = 0,01 P = 0,15 Acute and late toxicity: no difference Huguenin et al. JCO , 2004 Huguenin et al. JCO , 2004
German Cancer Society 95-06 Trial German Cancer Society 95-06 Trial RT + CT (C-HART) R 5FU + MMC + 70.6Gy A N=384 30Gy QD => 1.4Gy BID N Stage III – IV D SCC O M Oropharynx I RT Alone (HART) Hypopharynx Z 77.6Gy Oral cavity E 14Gy QD => 1.4Gy BID Budach et al. JCO , 2005 Budach et al. JCO , 2005
German Cancer Society 95-06 Trial German Cancer Society 95-06 Trial 5y-LRC 5y-OS 5y-DFS 5y-DMF C – HART 49.9% 28.6% 29.3% 51.9% HART 37.4% 23.7% 26.6% 54.7% P = 0.01 P = 0.02 P = 0.09 P = 0.57 Budach et al. JCO , 2005 Budach et al. JCO , 2005
Considerations about CT + Altered Fx RT Considerations about CT + Altered Fx RT � Results with CT + altered Fx RT are promising but is still not ideal � There is still no mature results from prospective and randomized trial comparing CT + AFx RT and CT + QD RT � We must be aware about toxicities with these combined treatment � In developing countries altered fractionated RT causes logistic problems � In the setting of CT, QD RT offers equal results with less toxicity than altered Fx
Question still remaining: Question still remaining: Employing concurrent CT+RT, is altered Employing concurrent CT+RT, is altered fractionated RT really necessary? fractionated RT really necessary? We must wait the final results of We must wait the final results of Ongoing GORTEC 99-02 and RTOG 0129 Trials Ongoing GORTEC 99-02 and RTOG 0129 Trials
GORTEC 99-02 GORTEC 99-02 QD RT + CT R 3 x Carbo / 5FU A N Acc RT + CT D Stage III – IV RT: 70Gy in 6 weeks O SCC CT: 2 x Carbo / 5FU M I Z Acc RT alone E 64.8Gy in 3.5 weeks 1.8Gy BID Bourhis et al. ASTRO 2008 Bourhis et al. ASTRO 2008
RTOG 0129 RTOG 0129 AFX – CB + CT R 72Gy in 6 weeks Stage III – IV A CDDP 100 mg/m 2 1 and 22 SCC N D Oral cavity O Oropharynx M Larynx I QD RT + CT Z Hypopharynx 70Gy in 35 fractions E CDDP 100 mg/m 2 1,22,43
Novel target therapies Novel target therapies
Rationale of targeting the EGFR Rationale of targeting the EGFR � EGFR is expressed in the vast majority of the Head & Neck tumors � Inverse relationship between prognostic and expression � Activity includes synergy with other therapies � Clinical trials have demonstrated activity in the disease � There are several ongoing RTOG prospective trials testing the effectiveness of cetuximab
RT + Cetuximab RT + Cetuximab Survival R RT Alone 29.3 months A Stage III – IV N SCC D Oropharynx O P =0.03 M Hypopharynx I Larynx Z RT + CTX 40 months E Bonner et al. NEJM , 2006 Bonner et al. NEJM , 2006
RT + Cetuximab RT + Cetuximab Bonner et al. NEJM , 2006 Bonner et al. NEJM , 2006
RT technology advances RT technology advances
External beam RT advances External beam RT advances CONVENTIONAL Gain: Safety CONFORMAL Gain: Safety and dose delivery IMRT Gain: Safety IGRT
IMRT in Head & Neck Cancer IMRT in Head & Neck Cancer � IMRT is the most important RT advance in the � IMRT is the most important RT advance in the treatment of H&N cancer treatment of H&N cancer � Capability to deliver concentrated dose at the target � Capability to deliver concentrated dose at the target volumes at same time sparing adjacent normal volumes at same time sparing adjacent normal tissues tissues � Possibility of different prescribed daily doses at � Possibility of different prescribed daily doses at distinct and close structures distinct and close structures � Potential of better local control and lower toxicity � Potential of better local control and lower toxicity � Quicker overall treatment time � Quicker overall treatment time � Spinal cord protection with posterior electron fields boost and separated supraclavicular field are not necessary
IMRT fields IMRT fields 5 4 6 3 7 2 1
IMRT fields IMRT fields
Dose distribution with IMRT Dose distribution with IMRT GTV: 30 x 2.2Gy=66Gy CTV1: 30 x 2.0Gy=60Gy CTV2: 30 x 1.8Gy=54Gy
Dose distribution with IMRT Dose distribution with IMRT
Parotid sparing with IMRT Parotid sparing with IMRT 20 Gy 70 Gy 40 Gy 60 Gy Courtesy: Clifford Chao (MDACC)
Dose distribution – RTOG 0022 Dose distribution – RTOG 0022 GTV: 30 x 2.2Gy=66Gy CTV1: 30 x 1.8Gy=54Gy
Dose distribution with IMRT Dose distribution with IMRT
IMRT – Nasopharynx cancer IMRT – Nasopharynx cancer N Stage Median LC Reference Follow up Lee et al. (UCSF) 67 All 31 m 97% 4 years Int J Radiat Oncol Biol Phys. 2002 Kwong et al. (Hong Kong) 50 T3-4 25 m 96% 2 years Int J Radiat Oncol Biol Phys. 2006 Kam et al. (Hong Kong) 64 All 29 m 92% 3 years Int J Radiat Oncol Biol Phys. 2004 Wolden et al. (MSKCC) 74 All 35 m 91% 3 years Int J Radiat Oncol Biol Phys. 2006 Chua et al. (Hong Kong) 31 Recurrence 11 m 58% Radiother Oncol. 2005
IMRT – Oropharynx cancer IMRT – Oropharynx cancer Author N Stage CT Survival CL Chao 74 III 23% 40 m 95% 4 y Garden 51 I/II 14% 18 m 92% 2 y Huang 41 III/IV 73% 20 m 92% 2 y Eisbruch 80 III/IV 50% 32 m 94% 3 y De Arruda 50 III/IV 86% N 98% 2 y
Oropharynx cancer Oropharynx cancer IMRT Vs non-IMRT IMRT Vs non-IMRT Patient No. Median F/U 2yr LRC 2yr DFS Def. Non-IMRT 153 3.5 yr (1.6-17.7) 68.3% 58.4% Def. IMRT 31 3 yr (12-58) 87.5% 73.5% Post-op Non-IMRT 142 3.9 yr (1.3-19.8) 75.7% 73.5% Post-op IMRT 43 2.8 yr (9-60) 95.0% 94.3% Data compiled from Chao et al. Radiotherapy & Oncology, 61:275, 2001 and Chao et al. IJROBP 59:43-50, 2004
Results of toxicity Results of toxicity Grade 2-3 POS-OPERATIVE RTC-3D IMRT Skin 16% 8% Mucositis 18% 0% Xerostomy 77% 17% Osteonecrosis 3% 0% Necrosis 1% 0% Chao KS Radiother Oncol 2001;61:275-84
Results of toxicity Results of toxicity RT Alone Grade 2-3 RTC-3D IMRT Skin 17% 10% Mucositis 12% 10% Xerostomy 84% 30% Osteonecrosis 7% 0% Necrosis 1% 0% Chao KS Radiother Oncol 2001;61:275-84
GORTEC 2004 - 01 GORTEC 2004 - 01 CONVENTIONAL RT R 70Gy + CDDP A Oral cavity N Oropharynx D O SCC M I Stages I - IV IMRT Z 75Gy + CDDP E Endpoints: Xerostomy, local control Endpoints: Xerostomy, local control
Hands- -on IMRT training on IMRT training Hands Hands-on IMRT training Hospital Israelita Israelita Albert Einstein Albert Einstein Hospital Hospital Israelita Albert Einstein
Hands- -on IMRT training on IMRT training Hands Hands-on IMRT training Hospital Israelita Israelita Albert Einstein Albert Einstein Hospital Hospital Israelita Albert Einstein
Conclusions Conclusions � The combination of CT and RT improves overall survival and local � The combination of CT and RT improves overall survival and local control in H&N cancer, especially if concomitant association is control in H&N cancer, especially if concomitant association is employed employed � The most effective combined treatment for locally advanced � The most effective combined treatment for locally advanced 2 every 3 weeks tumors is RT + CDDP 100mg/m 2 every 3 weeks tumors is RT + CDDP 100mg/m � There is no benefit of weekly CDDP concomitant with RT when � There is no benefit of weekly CDDP concomitant with RT when compared to RT alone compared to RT alone � Induction CT followed by RT alone is less effective than � Induction CT followed by RT alone is less effective than concomitant association concomitant association � Induction poly � Induction poly- -CT based on CT based on taxanes taxanes followed by RT+CT is under followed by RT+CT is under investigation investigation � Poly � Poly- -CT is still not better than mono CT is still not better than mono- -CT CT
Conclusions Conclusions � The best altered fractionated RT regimen is � The best altered fractionated RT regimen is HPx HPx but is not better but is not better than QD RT + CT. This strategy can be used in patients with locally lly than QD RT + CT. This strategy can be used in patients with loca advanced tumors and who can not receive CT advanced tumors and who can not receive CT � The association of CT with altered fractionated RT might boost t � The association of CT with altered fractionated RT might boost the he effect or CT+RT, but this benefit has still to be proven effect or CT+RT, but this benefit has still to be proven � The most effective regimen of adjuvant treatment for high risk � The most effective regimen of adjuvant treatment for high risk patients is the combination of RT and CDDP patients is the combination of RT and CDDP � RT associated with � RT associated with cetuximab cetuximab improves local control and survival, improves local control and survival, but is not still proven that is better than association of RT + CDDP CDDP but is not still proven that is better than association of RT + � IMRT is the most important advances in RT techniques due to the � IMRT is the most important advances in RT techniques due to the better dose delivered and possibility of simultaneous boost better dose delivered and possibility of simultaneous boost strategy strategy
Cervical cancer Cervical cancer Cervical cancer
Radiochemotherapy combination Radiochemotherapy combination for cervical cancer for cervical cancer • 5 randomized trial since 1999 Increase 10 - 15% in survival • Clinical alert (NCI) “Strong consideration should be given to the incorporation of concurrent chemotherapy with radiation therapy for cervical cancer”
GOG-85 / SWOG 8695 GOG-85 / SWOG 8695 N 3y OS p p R 191 RT + HU 57% A N D IIB-IVA O M I Z 177 RT + 5 FU/CDDP 67% 0.03 E D Whitney CW et al: J Clin Oncol 17:1339, 1999
GOG 120 GOG 120 N 3y OS p p R 177 A RT+HU 47% N D IIB-IVA O 65% 176 RT+CDDP 0.57 <0.001 M I Z RT+HU + 5FU+CDDP 173 65% <0.001 E D Rose PG, et al NEJM 340:1144, 1999
GOG 123 GOG 123 N 3y OS p p R RT → EF hyst A 191 74% N IB ≥ 4cm D O N - M I Z RT+CDDP → EF hyst 177 83% 0.03 E D Keys HM, et al: NEJM 340:1154, 1999
RTOG 90-01 RTOG 90-01 N 3y OS p p R A 195 RT (Pelvis + PAo) 63% N D IB 1 (N+) O IB 2 -IVA M PAo - I Z 194 RT + 5 FU/CDDP 75% <0.001 E D Morris M, et al: NEJM 340:1137, 1999 *updated ASTRO 2002 5y OS - 72% x 52%
RTOG 90- -01 01 RTOG 90 RTOG 90-01 N 8y OS p p R A 195 RT (Pelvis + PAo) 41% N D IB 1 (N+) O IB 2 -IVA Stage III - IVA: 59% Vs 47%; p =0.066 M PAo - I Z 194 RT + 5 FU/CDDP 67% <0.001 E D Eifel et al. JCO 22:2004
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