Debate:Neoadjuvant Chemotherapy

versus Primary Radiochemotherapyin FIGO IB2 Cervical Cancer

Neoadjuvant chemotherapy

Giovanni Aletti, MDEuropean Institute of Oncology

Milan, Italy

Stage IB2 Cervical CancerRound 1

Chemoradiation

NACT surgery

Locally Advanced Cervical Cancer

Different approaches:

- Chemo/radiation ± chemotherapy

- NACT ⇒ surgery ± chemo/radiation

- Surgery ± chemo/radiation

ALL TREATMENTS REQUIRE A MULTIMODALITY APPROACH

Locally Advanced Cervical CancerWORLDWIDE…

- CT/RT is considered standard of care

- 1999 NCI announcement:

“The results of 5 large studies have shown that women with invasive cervical cancer have better survival when they receive chemotherapy which includes the drug cisplatin along with radiation therapy.”

Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration (CCCMAC). Cochrane Database Syst Rev. 2010;(1):CD008285.

Locally Advanced Cervical Cancer

• HR correlated withstage

• HR similar for CDDP and non CDDP-basedchemo-RT

• HR best for two trials with concurrent and adjuvant CT

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

Locally Advanced Cervical Cancer

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

Locally Advanced Cervical Cancer

Locally Advanced Cervical CancerNACT & S vs RT

Favors NACT-S Favors RT

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

• Stage Ib2-IIb• Stage IIIb

Randomized RT: 214 patients

NACT+S: 227 patients

Benedetti-Panici P, et al. J Clin Oncol. 2002;20(1):179-188.

• 210/227 (NACT) and 199/214 (RT) patients eligible• Stage IB2-IIA (174 pt); IIB (148 pt); III (87 pt) well balanced in the 2 ARMS• 152 (NACT) and 144 (RT) received treatment according to protocol

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer:

Results From the Italian Multicenter Randomized Study

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer:

Results From the Italian Multicenter Randomized Study

0

10

20

30

40

50

60

70

80

90

100

6 12 18 24 30 36 42 48 54 60

Prob

abili

ty

Months

NACT + RSRT

Pts Events210 84 199 100

P value: .001

100

60

10

20

30

40

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54

NACT + RSRT

Pts Events210 84 199 100

P value: .01

Prob

abili

ty

Months

Benedetti-Panici P, et al. J Clin Oncol. 2002;20(1):179-188.

Criticisms to the Italian RCT

ARM 1: RADIOTHERAPY 27% of patients had external radiotherapy only

ERT+BRT total dose was less than 70 Gy

82% of patients received RT not on time (>55 days)

OTHER ISSUES

38/164 patients received RT after RS (3 modalities)

No benefit for stage III

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study

1. Chemoradiation is better than radiation alone in the treatment of LACC

2. NACT-radical surgery is better than radiation alone in the treatment of LACC

3. In stage III NACT-radical surgery is not helpful

SO…CHEMORADIATION OR NACT-RADICAL SURGERY?

What Have We Learned So Far?Take-Home Messages (Round 1)

IT LOOKS LIKE A TIED GAME…

EORTC - 55994RCT Comparing NACT+RS Versus CT/RT

RANDOMIZED

NACT + SURGERY

ExclusiveChemoradiation

Cervical CancerIB2, IIA>4 cm, IIB

While Awaiting the Results of EORTC 55994…

Use your weapons in different ways!!!

Stage IB2 Cervical CancerRound 2

Stage IB2 cervical cancer

NACT…how?

Locally Advanced Cervical Cancer

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

Locally Advanced Cervical CancerNACT & RT vs RT

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

Locally Advanced Cervical CancerNACT & RT vs RT

Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD001774.

The Cochrane Review Indicated That:

Trials using cycle lengths shorter than 14 days or the cisplatin dose greater than 25mg/m2 per week exhibited an advantage of NACT on the survival of patients with LACC. It indicates that the timing and dose intensity may greatly impact the curative effect of NACT.

Round 2: NACT…how?When you do it…do it right!!!

Be fast…and intense!!! Use DOSE-DENSE

Stage IB2 Cervical CancerRound 3 – potential advantages

NACT

Stage IB2 cervical cancer

Rydzewska L, et al. Cochrane Database Syst Rev. 2010;(1):CD007406.

Locally Advanced Cervical Cancer

Locally Advanced Cervical Cancer• Better OS and PFS for

NACT/RS vs RS• Fewer local recurrences• Fewer distant

recurrences• More radical resections• Less N +• Less parametrial

involvement

Rydzewska L, et al. Cochrane Database Syst Rev. 2010;(1):CD007406.

POTENTIAL ADVANTAGES OF NACT 1. Reduction of tumor burden Biologic marker of

aggressiveness

2. Potential decrease of distant metastases

3. Potential eradication of micrometastases

4. Potential for better prognosis…

5. Identification of patients requiring multimodality approach

What Have We Learned So Far?Take Home Messages (Round 3)

Round 3: Potential advantages

Understand your rival first…Then we use the right strategy!!!

Stage IB2 Cervical CancerRound 4 – integration of strategies

Stage IB2 cervical cancer

NACT Chemoradiation

INduction ChemoThERapy in Locally Advanced CErvical Cancer

INTERLACE

Mary McCormack for the NCRI Gynaecological

Clinical Studies Group

INTERLACERandomize (IB2-IVA)

Carboplatin AUC2 & Paclitaxel 80 mg/m2

Weeks 1-6

Weeks 7-13Standard CRT

Standard CRT

Follow-up3 monthly for 2 years; 6 monthly for 3 years

Standard CRT : 40 Gy - 50.4 Gy in 20-28 fractions plus Intracavitary brachytherapy to give total EQD2 dose of 78-86Gy to point A/volume.Weekly cisplatin 40mg/m2 x 5 weeks

Induction Chemotherapy

Week 1 2 3 4 5 6

CarboplatinAUC2 • • • • • •

Paclitaxel 80mg/m2 • • • • • •

Paclitaxel and carboplatin—weekly treatment for six weeks

Chemoradiation

Cisplatin weekly treatment for five weeks

Week 7 8 9 10 11 12

Days 1-5 8-12 15-19 22-26 29-33 36-40

Radiotherapy:40-50.4 Gy in20-28 fractions

• • • • • • • • • • • • • • • • • • • • • • • • • • • •

Cisplatin 40 mg/m2 • • • • •

Stratification

• FIGO stage• Node status—positive/negative• Tumor volume• Squamous vs nonsquamous• IMRT vs no IMRT• Age• Recruiting site

Outcome MeasuresPrimary endpoint: OS at 5 years

Secondary endpoints: PFS Toxicity QOL (UK & Eire only) Pattern of relapse (local and/or systemic)

Stage IB2: Role of NACT

Dose-dense chemo

No response

Chemo-RT

Response

Lymphadenectomy(staging or curative?)

Positive nodes

Negative nodes

Radical surgery

Round 4: NACT different strategies

Ok use your weapons right!We know, your rival is tired now!

• Is NACT a reasonable approach for patients with stage IB2 cervical cancer? – YES but…do it right (DOSE DENSE)

• Is NACTsurgery superior to definitive chemoradiation? – Waiting the EORTC results

• Is NACTCRT superior to definitive chemoradiation?– Waiting for the INTERLACE trial

• Can prognosis of patients with stage IB2 be improved?– Better selection strategies– Better biology/definition– Multimodality approach– Adjuvant chemotherapy– New modalities (targeted therapies, immunotherapy,...)– Extended field irradiation

Conclusions—Stage IB2

THANKS!