Advances in Chemo-RT for cervical and Advances in Chemo-RT for - - PowerPoint PPT Presentation

Advances in Chemo-RT for cervical and Head & Neck cancer Advances in Chemo-RT for cervical and Head & Neck cancer

International Conference on Advances in Radiation Oncology (ICAR International Conference on Advances in Radiation Oncology (ICARO) O) 27 27-

• 29 April 2009

29 April 2009 Vienna, Austria Vienna, Austria

Robson Ferrigno Hospital Israelita Albert Einstein São Paulo – Brazil Robson Robson Ferrigno Ferrigno Hospital Israelita Albert Einstein Hospital Israelita Albert Einstein São Paulo São Paulo – – Brazil Brazil

• Worldwide: > 500,000 new cases per year

Worldwide: > 500,000 new cases per year

• The fifth most common neoplasm

The fifth most common neoplasm

• 5% of newly diagnosed cancers in adults

5% of newly diagnosed cancers in adults

• 60% present with locally or regionally advanced

60% present with locally or regionally advanced disease (stages III or IV) disease (stages III or IV)

• Mortality rate of > 300,000 death per year

Mortality rate of > 300,000 death per year

• The majority of cured patients has considerable

The majority of cured patients has considerable late toxicity late toxicity

• Locally advanced disease: 5

Locally advanced disease: 5-

• year OS 30

year OS 30 – – 50% 50%

Head & Neck Cancer Head & Neck Cancer

What is the main goal in the What is the main goal in the treatment of H & N cancer? treatment of H & N cancer? To maximize the combination of To maximize the combination of curability and quality of life curability and quality of life

Head & Neck Cancer Head & Neck Cancer

• 1. Surgery
• 2. Radiation Therapy
• 3. Chemotherapy
• 4. Novel targeted therapies
• 5. Combination of 2 or 3 modalities

Head & Neck Cancer

Treatments available

Head & Neck Cancer

Treatments available

Surgery is preferred for initial diseases but can cause function disability or poor cosmetic results Traditional treatment for unresectable disease involves radiation therapy alone, but the results are very poor with control rates lower than 20%

Head & Neck Cancer

Treatment

Head & Neck Cancer

Treatment

How can we increase the cure rates for locally advanced diseases at same time preserving the organs and maintaining acceptable toxicity?

Head & Neck Cancer

Treatment

Head & Neck Cancer

Treatment

• 1. Combination of RT and CT
• 2. Altered fractionated RT
• 3. Altered fractionated RT and CT
• 4. Novel target therapies
• 5. RT technology advances

Head & Neck Cancer

Topics of treatment advances

Head & Neck Cancer

Topics of treatment advances

Combined RT and CT Combined RT and CT

• 19 randomized trials evaluated
• Objective: establish the relationship between

loco-regional control and OS

• 10% improvement in 2-year loco-regional control

increase 5-year OS in 6.7%

• Limitation of RT in terms of dose escalation

without causing excessive complications

• Addition of CT or new target agents may increase

the results

Meta-analysis Meta-analysis

Wadsley et al. Red J, 2004 Wadsley et al. Red J, 2004

• Sensitize hypoxic tumor cells to radiation
• Inhibit tumor repopulation
• Enhance radiation induced apoptosis
• Inhibit repair of radiation damage
• Synchronization and redistribution of tumor cells

into more sensitive G2-M cell-cycle phase

• Decrease the tumor mass leading to improved

blood supply and increased radiosensitivity caused by reoxygenation

• Sterilize micrometastases outside the radiation

fields

The rationale of adding CT to RT The rationale of adding CT to RT

Evidence-based medicine for combined RT and CT Evidence-based medicine for combined RT and CT

Singapore randomized trial Singapore randomized trial

Stage III / IV SCC Oral cavity Oropharynx Larynx Hipopharynx Max Sinus R A N D O M I Z E

Surgery + RT 60 – 70 Gy CT + RT 2 x CDDP/5-FU + 66 Gy

Soo et al. Br J Cancer 2005 Soo et al. Br J Cancer 2005

3-year DFS: 50% Vs 40% Surgical complication rate: 27% Organ preservation rate: 45% For larynx/hypopharynx preservation was higher: 68% Vs 30%

Singapore trial Singapore trial

Soo et al. Br J Cancer 2005 Soo et al. Br J Cancer 2005

Intergroup Trial Intergroup Trial

295 Stage III – IV Oropharynx Larynx Hypopharynx Oral cavity R A N D O M I Z E

RT + CT (5FU+CDDP) RT alone (70Gy)

Aldelstein et al. JCO, 2003 Aldelstein et al. JCO, 2003

RT + CT (CDDP)

CDDP: 100mg/m2 1,22,43

Follow up: 41 months

3y – OS MS

RT+5FU/CDDP

27%

P=0.014 RT+CDDP RT Alone

37% 23% 13.8 m 19.1 m 12.6 m

Adelstein et al. JCO, 2003 Adelstein et al. JCO, 2003

Intergroup Trial Intergroup Trial

RTOG 91-11 Larynx preservation trial RTOG 91-11 Larynx preservation trial

Glottic supraglottic T2 – T3 Early T4 N0 – N3 R A N D O M I Z E

Neoadjuvant CT => RT RT alone (70Gy)

Forastiere et al. NEJM, 2003 Forastiere et al. NEJM, 2003

RT + CT (CDDP)

CDDP: 100mg/m2 1,22,43 CT: CDDP/5FU

RTOG 91-11

Larynx preservation trial

RTOG 91-11

Larynx preservation trial

Forastiere et al. NEJM, 2003 Forastiere et al. NEJM, 2003

84% 71% 66%

RTOG 91-11

Larynx preservation trial

RTOG 91-11

Larynx preservation trial

Forastiere et al. NEJM, 2003 Forastiere et al. NEJM, 2003

RTOG 91-11

Larynx preservation trial

RTOG 91-11

Larynx preservation trial

Forastiere et al. NEJM, 2003 Forastiere et al. NEJM, 2003

INTERGROUP 99 (RTOG 88-17) INTERGROUP 99 (RTOG 88-17)

NPC Stage III / IV M0 AJCC (1992) R A N D O M I Z E

RT alone (70 Gy) RT + CT (3 x CDDP) CDDP + 5FU

Al-Sarraf et al. JCO, 1998 Al-Sarraf et al. JCO, 1998

Follow up: minimum of 5 years RT RT + QT

5y PFS

P<0.001

29%

P<0.001 P<0.001

5y DFS 5y OS 46% 37% 58% 74% 67%

Al-Sarraf et al. JCO, 1998 Al-Sarraf et al. JCO, 1998

INTERGROUP 99 (RTOG 88-17) INTERGROUP 99 (RTOG 88-17)

10 randomized trials evaluated 4% increase in 5-year OS with addition of CT Largest effects with concomitant regimens (20% increase in OS) Other Meta-analysis showed the same results

Meta-analysis

CT+RT for NPC

Meta-analysis

CT+RT for NPC

Langendijk J.A. JCO, 2004 Langendijk J.A. JCO, 2004

Adjuvant treatment

Is there a benefit of CT added to RT course?

Adjuvant treatment

Is there a benefit of CT added to RT course?

Two prospective randomized trials: EORTC 22931 and RTOG 9501

Adjuvant treatment: RT Vs RT+CT

Two prospective randomized trials: EORTC 22931 and RTOG 9501

Adjuvant treatment: RT Vs RT+CT

EORTC 22931 EORTC 22931

N=334 Stages III – IV Operable Oral cavity Oropharynx Larynx Hipopharynx R A N D O M I Z E

RT alone (66 Gy) RT + CT

CDDP 100mg/m2 1,22,43 Bernier et al. NEJM, 2004 Bernier et al. NEJM, 2004

Follow up: 60 months

RT RT + QT

5y DFS

P=0.04

36%

P=0.02 P=0.007

5y OS 5y LC 40% 69% 47% 53% 82%

EORTC 22931 EORTC 22931

Bernier et al. NEJM, 2004 Bernier et al. NEJM, 2004

EORTC 22931 EORTC 22931

Bernier et al. NEJM, 2004 Bernier et al. NEJM, 2004

EORTC 22931 EORTC 22931

Bernier et al. NEJM, 2004 Bernier et al. NEJM, 2004

RTOG 9501 RTOG 9501

N=459 ≥ 2 LNs+ ECE Margin +

R A N D O M I Z E

RT alone (60 – 66 Gy) RT + CT

CDDP 100mg/m2 1,22,43 Cooper et al. NEJM, 2004 Cooper et al. NEJM, 2004

Follow up: 46 months

RT RT + QT

5y DFS

P=0.04

61%

P=0.19 P=0.01

5y OS 5y LC 57% 72% 78% 63% 82%

RTOG 9501 RTOG 9501

Cooper et al. NEJM, 2004 Cooper et al. NEJM, 2004

Cooper et al. NEJM, 2004 Cooper et al. NEJM, 2004

RTOG 9501 RTOG 9501

Cooper et al. NEJM, 2004 Cooper et al. NEJM, 2004

RTOG 9501 RTOG 9501

What about induction CT? What about induction CT?

Decrease the risk of distant metastasis Improve overall survival Recognize the response to CT which is predictive of a response to RT Decrease the tumor volume to improve the RT treatment planning

Why induction CT? Why induction CT?

• There are at least 31 randomized trials with

induction CT

• Drugs used include cisplatin, 5-Fu, bleomycin, MTX,

VCR, Mytomicin-C, and more recently, taxanes

• Response rates to induction CT with CDDP and

5FU: up to 90% and complete response ~ 30%

• No benefit has been proven in induction CT

followed by radiation alone

• There is no trial comparing induction CT followed

by RT and induction CT followed by RT+CT

• Induction CT based on taxanes

followed by concomitant RT+CT is under investigation

Induction CT for H &N cancer Induction CT for H &N cancer

Phase III Trial for Neo Adjuvant CT Phase III Trial for Neo Adjuvant CT

Stage III – IV SCC Oral cavity Oropharynx Hypopharynx Sinus R A N D O M I Z E Neo Adjuvant CT 5FU + CDDP x 4 Surgery + RT (50Gy) or RT (65 – 70 Gy) Zorat et al. JNCI, 2004 Zorat et al. JNCI, 2004 Surgery + RT or RT

Median follow up: 12.5 years

CT + RT RT

5y OS 23% 10y OS p 19% 16% 9% 0.13

Phase III Trial for Neoadjuvant CT Phase III Trial for Neoadjuvant CT

Zorat et al. JNCI, 2004 Zorat et al. JNCI, 2004

• 1. Induction CT would decrease the risk of

distant metastasis

• 2. Concurrent RT + CT would improve loco-

regional control

Why induction CT => RT+CT? Why induction CT => RT+CT?

Spanish trial Spanish trial

382 Stage III – IV SCC Oral cavity Oropharynx Hypopharynx

R A N D O M I Z E

CDDP 100 mg/m2 5FU 1 g/m2 Paclitaxel 175 mg/m2 CDDP 100 mg/m2 5FU 500 mg/m2

Hitt et al. JCO, 2005 Hitt et al. JCO, 2005

Spanish trial Spanish trial

RT (70Gy) CDDP (100 mg/m2) CR or PR > 80%

Median follow up: 2 years

193: CF 189: PCF

CR 14% OS

Mucositis 37 months

33%

43 months 16%

Spanish trial Spanish trial

P < 0,001 P = 0,06 P = 0,06

53% Hitt et al. JCO, 2005 Hitt et al. JCO, 2005

Spanish trial

Overall Survival for unresectable disease

Spanish trial

Overall Survival for unresectable disease

Hitt et al. JCO, 2005 Hitt et al. JCO, 2005

36 m Vs 26 m; p=0,04 PCF CF

Spanish trial Spanish trial

Hitt et al. JCO, 2005 Hitt et al. JCO, 2005

What is best timing and scheme of CT in Head & Neck cancer when combined with RT or Surgery? What is best timing and scheme of CT in Head & Neck cancer when combined with RT or Surgery?

Updated: Bourhis at ASCO 2004

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

The main Meta-analysis - Findings The main Meta-analysis - Findings

Pignon et al. The Lancet, 2000 Pignon et al. The Lancet, 2000

The main Meta-analysis - Findings The main Meta-analysis - Findings

Pignon et al. The Lancet, 2000 Pignon et al. The Lancet, 2000 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%

CT Control

Courtesy of Jean Bourhis Courtesy of Jean Bourhis

• 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

MACH – NC update MACH – NC update

Bourhis et al. JCO, 2004 Bourhis et al. JCO, 2004

What is the best platin-based CT administration schedule during concurrent RT?

Daily? Weekly? Every 3 weeks?

What is the best platin-based CT administration schedule during concurrent RT?

Daily? Weekly? Every 3 weeks?

• The main trials that have proven the benefit of

concurrent CDDP with RT have used dose of 100 mg/m2 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

Platin schedule administration Platin schedule administration

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)

• 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)

Altered fractionated RT Altered fractionated RT

Bourhis et al. Lancet, 2006 Bourhis et al. Lancet, 2006 Fu et al. Red J, 2000 Fu et al. Red J, 2000

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 All groups All groups HPX HPX

What about altered fractionated RT + CT? What about 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?

Altered fractionated RT + CT Altered fractionated RT + CT

Duke Randomized Trial Duke Randomized Trial

N=122 Stage III – IV Oropharynx Hypopharynx Oral cavity NPC Sinus R A N D O M I Z E

HFX + CT 70Gy 1.25 BID 2 x CDDP + 5FU (Split course) HFX Alone 75Gy 1.25 BID

Brizel et al. NEJM, 1998 Brizel et al. NEJM, 1998

Duke Randomized Trial Duke Randomized Trial

Brizel et al. NEJM, 1998 Brizel et al. NEJM, 1998

Median follow up: 41 months

RT + CT RT 5y-LRC 70% 5y-DFS Tox G III 60% 44% 40% 75%

Duke Randomized Trial Duke Randomized Trial

P = 0.01 P = 0.08 P = 0.07

77% Hitt et al. Uptaded at ASTRO 2007 Hitt et al. Uptaded at ASTRO 2007 5y-OS 42% 28%

Switzerland Randomized Trial Switzerland Randomized Trial

N=224 Stage III – IV SCC Oropharynx Hypopharynx Larynx R A N D O M I Z E HFX Alone 74.4Gy 1.2 BID HFX + CT 74.4Gy 1.2 BID 2 x CDDP (20mg/m2) W1 and W5 Huguenin et al. JCO, 2004 Huguenin et al. JCO, 2004

RT + CT RT 5y-LC 64% 5y-LRC 5y-OS 51% 36% 33% 32%

Switzerland Randomized Trial Switzerland Randomized Trial

P = 0.01 P = 0.04 P = 0,01

46% 5y-DMF 61% 40% Huguenin et al. JCO, 2004 Huguenin et al. JCO, 2004

P = 0,15

Acute and late toxicity: no difference

German Cancer Society 95-06 Trial German Cancer Society 95-06 Trial

N=384 Stage III – IV SCC Oropharynx Hypopharynx Oral cavity R A N D O M I Z E RT + CT (C-HART) 5FU + MMC + 70.6Gy 30Gy QD => 1.4Gy BID RT Alone (HART) 77.6Gy 14Gy QD => 1.4Gy BID Budach et al. JCO, 2005 Budach et al. JCO, 2005

C – HART HART 5y-LRC 49.9% 5y-OS 5y-DMF 28.6% 37.4% 23.7% 54.7%

P = 0.01 P = 0.02 P = 0.09

51.9% 5y-DFS 29.3% 26.6%

P = 0.57

German Cancer Society 95-06 Trial German Cancer Society 95-06 Trial

Budach et al. JCO, 2005 Budach et al. JCO, 2005

• 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

Considerations about CT + Altered Fx RT Considerations about CT + Altered Fx RT

Question still remaining:

Employing concurrent CT+RT, is altered fractionated RT really necessary?

We must wait the final results of Ongoing GORTEC 99-02 and RTOG 0129 Trials

Question still remaining:

Employing concurrent CT+RT, is altered fractionated RT really necessary?

We must wait the final results of Ongoing GORTEC 99-02 and RTOG 0129 Trials

R A N D O M I Z E QD RT + CT 3 x Carbo / 5FU Acc RT alone 64.8Gy in 3.5 weeks 1.8Gy BID

Bourhis et al. ASTRO 2008 Bourhis et al. ASTRO 2008

Acc RT + CT RT: 70Gy in 6 weeks CT: 2 x Carbo / 5FU

GORTEC 99-02 GORTEC 99-02

Stage III – IV SCC

RTOG 0129 RTOG 0129

Stage III – IV SCC Oral cavity Oropharynx Larynx Hypopharynx R A N D O M I Z E AFX – CB + CT 72Gy in 6 weeks CDDP 100 mg/m2 1 and 22 QD RT + CT 70Gy in 35 fractions CDDP 100 mg/m2 1,22,43

Novel target therapies Novel target therapies

• 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

Rationale of targeting the EGFR Rationale of targeting the EGFR

RT + Cetuximab RT + Cetuximab

Stage III – IV SCC Oropharynx Hypopharynx Larynx R A N D O M I Z E RT Alone RT + CTX

Survival

29.3 months 40 months P=0.03

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

CONVENTIONAL CONFORMAL IMRT

IGRT External beam RT advances External beam RT advances

Gain: Safety Gain: Safety and dose delivery Gain: Safety

• 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 in Head & Neck Cancer IMRT in Head & Neck Cancer

4 6 5 7 3 2 1

IMRT fields IMRT fields

IMRT fields IMRT fields

GTV: 30 x 2.2Gy=66Gy CTV2: 30 x 1.8Gy=54Gy

Dose distribution with IMRT Dose distribution with IMRT

CTV1: 30 x 2.0Gy=60Gy

Dose distribution with IMRT Dose distribution with IMRT

20 Gy 60 Gy 40 Gy 70 Gy Courtesy: Clifford Chao (MDACC)

Parotid sparing with IMRT Parotid sparing with IMRT

GTV: 30 x 2.2Gy=66Gy CTV1: 30 x 1.8Gy=54Gy

Dose distribution – RTOG 0022 Dose distribution – RTOG 0022

Dose distribution with IMRT Dose distribution with IMRT

Reference

N Stage Median Follow up

LC

Lee et al. (UCSF)

Int J Radiat Oncol Biol Phys. 2002

67 All 31 m 97% 4 years Kwong et al. (Hong Kong)

Int J Radiat Oncol Biol Phys. 2006

50 T3-4 25 m 96% 2 years Kam et al. (Hong Kong)

Int J Radiat Oncol Biol Phys. 2004

64 All 29 m 92% 3 years Wolden et al. (MSKCC)

Int J Radiat Oncol Biol Phys. 2006

74 All 35 m 91% 3 years Chua et al. (Hong Kong)

Radiother Oncol. 2005

31 Recurrence 11 m 58%

IMRT – Nasopharynx cancer IMRT – Nasopharynx 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

IMRT – Oropharynx cancer IMRT – Oropharynx cancer

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

Oropharynx cancer

IMRT Vs non-IMRT

Oropharynx cancer

IMRT Vs non-IMRT

POS-OPERATIVE

Grade 2-3 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

Chao KS Radiother Oncol 2001;61:275-84

RT Alone Grade 2-3 RTC-3D IMRT Skin 17% 10% Mucositis 12% 10% Xerostomy 84% 30% Osteonecrosis 7% 0% Necrosis 1% 0%

Results of toxicity Results of toxicity

GORTEC 2004 - 01 GORTEC 2004 - 01

Oral cavity Oropharynx SCC Stages I - IV R A N D O M I Z E CONVENTIONAL RT 70Gy + CDDP IMRT 75Gy + CDDP Endpoints: Xerostomy, local control Endpoints: Xerostomy, local control

Hands-on IMRT training

Hospital Israelita Albert Einstein

Hands Hands-

• on IMRT training
• n IMRT training

Hospital Hospital Israelita Israelita Albert Einstein Albert Einstein

Hands-on IMRT training

Hospital Israelita Albert Einstein

Hands Hands-

• on IMRT training
• n IMRT training

Hospital Hospital Israelita Israelita Albert Einstein Albert Einstein

• 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 tumors is RT + CDDP 100mg/m tumors is RT + CDDP 100mg/m2

2 every 3 weeks

every 3 weeks

• 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 loca than QD RT + CT. This strategy can be used in patients with locally lly 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 + but is not still proven that is better than association of RT + CDDP CDDP

• 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

Conclusions Conclusions

Cervical cancer Cervical cancer Cervical cancer

Radiochemotherapy combination for cervical cancer Radiochemotherapy combination for cervical cancer

• 5 randomized trial since 1999

Increase 10 - 15% in survival

• Clinical alert (NCI)

“Strong consideration should be given to the incorporation

• f

concurrent chemotherapy with radiation therapy for cervical cancer”

GOG-85 / SWOG 8695 GOG-85 / SWOG 8695

IIB-IVA

R A N D O M I Z E D

RT + HU RT + 5 FU/CDDP N 191 177

p p

0.03

Whitney CW et al: J Clin Oncol 17:1339, 1999

3y OS 57% 67%

GOG 120 GOG 120

IIB-IVA

R A N D O M I Z E D RT+HU RT+HU+5FU+CDDP

N

177 173

p p

<0.001

Rose PG, et al NEJM 340:1144, 1999

RT+CDDP 176

0.57 <0.001 3y OS 47% 65%

65%

GOG 123 GOG 123

IB≥4cm N -

R A N D O M I Z E D

RT → EF hyst RT+CDDP → EF hyst

N 191 177

p p

0.03

Keys HM, et al: NEJM 340:1154, 1999

3y OS 74% 83%

RTOG 90-01 RTOG 90-01

IB1 (N+) IB2

• IVA

PAo -

R A N D O M I Z E D

RT (Pelvis + PAo) RT + 5 FU/CDDP N 195 194

p p

<0.001

Morris M, et al: NEJM 340:1137, 1999

3y OS 63% 75%

*updated ASTRO 2002 5y OS - 72% x 52%

IB1 (N+) IB2

• IVA

PAo -

R A N D O M I Z E D

RT (Pelvis + PAo) RT + 5 FU/CDDP N 195 194

p p

<0.001 41% 67%

Eifel et al. JCO 22:2004

Stage III - IVA: 59% Vs 47%; p=0.066

RTOG 90-01 RTOG 90 RTOG 90-

• 01

01

8y OS

SWOG 87-97 SWOG 87-97

IB-IIA Surgery Pelvic N+ Margin +

• r PAoN+

R A N D O M I Z E D

RT RT + 5 FU/CDDP N 116 127 p p 0.007

Peters III WA, et al: J Clin Oncol 18:1606, 2000

4y OS 71% 81% 81%

Radiochemotherapy considerations Radiochemotherapy considerations

• Strong evidences in favor of combined

treatment

• All 5 trials mentioned used LDRB
• Is

chemotherapy really necessary if effective dose of radiation in a proper treatment time is delivered?

• Is association of HDRB and CT more

effective and as safe as HDRB alone?

NCI - Canada NCI - Canada

IB/IIA/ IIB>5cm III, IV or N+

R A N D O M I Z E D

RT RT + CDDP

N 127 126

p p

0.42

Pearcey M, et al: J Clin Oncol 20:966, 2002

3y OS 58% 62%

What is the best regimen of CT when combined with RT? What is the best regimen of What is the best regimen of CT when combined with RT? CT when combined with RT?

Meta-analysis Meta Meta-

• analysis

analysis

Meta-analysis Meta Meta-

• analysis

analysis

Absolute improvement in survival of 12%

CDDP No CDDP

GOG 165 Trial GOG 165 Trial GOG 165 Trial

• Prospective and randomized trial
• Weekly CDDP+RT Vs PVI 5FU+RT
• Closed early: 35% failure rate with 5FU
• Conclusion: 5/FU alone inferior to weekly CDDP

Trials with weekly CDDP + RT Trials with weekly CDDP + RT

Trial N Control Results

GOG 120 526 HU + RT +++ GOG 123 374 RT (Pre-op) +++ NCIC 259 RT

Trials with CDDP/5FU + RT Trials with CDDP/5FU + RT

Trial N Control Results

*RTOG 90-01 389 RT (EF) +++ *SWOG 87-97 243 RT (P-OP) +++ GOG 85 368 RT + HU + *CDDP 70 – 75 mg/m2 + 5FU 4g every 3 weeks CDDP/5U was never compared with weekly CDDP

RT considerations for cervical cancer RT considerations for cervical cancer RT considerations for cervical cancer

• Point A is a geometric reference and does

not consider the tumor volume

• More accuracy can be obtained with image

treatment planning for teletherapy and brachytherapy

• Perforation must be avoided
• MRI is the most precise image exam to show

the tumor volume and can be used for brachytherapy and teletherapy planning

Ultrasound guided applicators insertion Ultrasound Ultrasound guided guided applicators applicators insertion insertion

Tumor Extension before EBT Target Volume after EBT

GTV

HR CTV at brachytherapy at diagnosis

MRI based brachytherapy MRI based MRI based brachytherapy brachytherapy

Courtesy: Richard Potter – University of Vienna

Cervix cancer – IMRT Cervix Cervix cancer cancer – – IMRT IMRT

1,8 Gy 2,0 Gy

4y – LC 4y – OS

• Lanciano. Red J, 1991

EBRT

45%

EBRT+BRACHY

67%

Is brachytherapy necessary? Is Is brachytherapy brachytherapy necessary? necessary?

19% 46% LC

• Montana. Cancer, 1986

40% 52%

Can IMRT replace brachytherapy? Can IMRT replace Can IMRT replace brachytherapy brachytherapy? ?

• Brachytherapy is fixed to target
• With brachytherapy, there is a non-homogeneity dose

distribution, but the tumor volume receive a very high dose

• f radiation, which is an advantage
• With IMRT there is complex internal motion and necessity
• f set-up daily correction
• IMRT may underdose critical regions, like uterosacral

ligaments, parametrial tissues and uterine cavity

• Difficult with IMRT to adjust the dose distribution with

tumor response

• IMRT should be used exclusively only in patients with no

geometrical conditions for brachy applicators insertion

Cervix cancer

Treatment recomendations - guideline

Cervix Cervix cancer cancer

Treatment Treatment recomendations recomendations -

• guideline

guideline

• EBRT: 45 Gy whole pelvis - top border: L5-S1
• Parametrial boost top border – Bottom of SI joints
• Parametrial boost dose - IIB: 5 Gy, IIIB: 10 Gy
• HDR fractions: 5 x 6 Gy, 4 x 7 Gy, or 3 x 8 Gy
• Start HDR when tumor < 4 cm
• Chemotherapy: 40 mg/m2 x 5
• Overall treatment time: < 50 days
• 2 HDR/week if necessary
• Hg ≥

10 ng/dl

IAEA Experts panel

Design proposal for stages II / III Design proposal for stages II / III

week1 week2 week3 week4 week5 week6 week7 EBR xxxxx xxxxx xxxxx xxxxx xxxxx HDRB B B B B PM ppp pp CT # # # # #

EBR = 45 Gy at whole pelvis HDRB = 4 x 7 Gy at point A PM = 9 Gy with midline block at small pelvis CT = CDDP 40 mg/m2

Recent advances in cervix cancer to improve the outcomes Recent advances in cervix cancer to Recent advances in cervix cancer to improve the outcomes improve the outcomes

• IMRT for pelvic and paraortic external RT

before brachytherapy to decrease toxicity, especially for small bowell and bone marrow

• Brachytherapy based image
• PET/CT for better staging
• HPV vaccine to avoid cervix cancer
• Ongoing prospective

trials are testing the association of RT with cetuximab

rferrigno@uol.com.br rferrigno@uol.com.br rferrigno@uol.com.br Hospital Israelita Albert Einstein – São Paulo Hospital Israelita Albert Einstein Hospital Israelita Albert Einstein – – São Paulo São Paulo

Thank you Thank you Thank you

IGUAÇU FALLS - BRAZIL