marc bollet : role of radiation oncologist in neoadjuvant breast cancer treatment

Place et rôle du radiothérapeute dans le TNA Place of the radiotherapy in NA treatment

[email protected]

Jerusalem, 30th April 2014

Place et rôle du radiothérapeute dans le TNA Place of the radia9on oncologist in NA

treatment

[email protected]


Could it alter the locoregional strategy?

Could be part of the NeoAdjuvant treatment? -  Concurrently with HT? -  Concurrently with ChT?

How to improve the use of RT in the neoadjuvant setting? -  Better patient selection -  Better regimen Could RT replace surgery after neoadjuvant CT?

Conclusion

Why should a breast cancer patient meet a radiation in the neo-adjuvant setting?

Contra-‐indica9on for breast conserving treatment?

Contra-‐indica9on for breast conserving treatment? Pendulous breasts?

Grann et al., IJROBP 2000

Prone Lateral Decubitus

Campana et al., IJROBP 2005

Alterna9ve techniques

Contra-‐indica9on for breast conserving treatment? Pexctus Excavatum?

Alterna9ve techniques

Bollet et al. BJR 2006

Contra-‐indica9on for breast conserving treatment? Previous RT (Hodgkin Lymphoma)?

Haberer, et al. Bollet, IJROBP 2012

72 women with history of HL 32 BCS (44%) 17 Breast RT with ILD

Contra-‐indica9on for breast conserving treatment? Precluding heart or lung co-‐morbidi9es?

Deep Inspiration Breath-Hold

Irradiated lung & heart↓

CTV to PTV margin ↓

Synchronization

Saliou et al., Cancer Radiother 2005




Conclusion


Could RT be part of the NA treatment? In associa9on with HT?

Bollet et al. Radiotherapy&Oncology 2006

40% T4b and/or ≥ 70mm

Med age 71 years

5-OS 85%, 5-RFS 84%, 5-LC 97%




Conclusion


Could RT be part of the NA treatment? In associa9on with CT?

. H&N SCC +4% in 5-OS Pignon et al. Lancet 2000

. NSCLC +4% in 2-OS Schaake-Koning et al. NEJM 1992 . Cervix +6% in 5-OS Vale et al. JCO 2008 . Anal canal +18% 5-LRC Bartelink et al. JCO 1997

Radiochemotherapy

Models with proven efficacy

Spatial and temporal collaboration

. Rectum +10% 4-OS O’Connel et al. NEJM 1994

. Esophagus SCC +25% in 5-OS Cooper et al. JAMA 1999


N F-‐U Surg CT OS LRC Arcangeli 206 5 TCA CMFx6 NS NS IJROBP 2006 Rouësse 638 5 T/M-‐CA FEC60x4 Seq NS NS IJROBP 2006 FNCx4 Conco S for BCS

Toledano 695 5 TCA FNCx6 NS NS JCO 2006 S for pN1

3 randomized studies on concomitant vs sequential radiochemotherapy in the adjuvant setting for BC


LRC Breast-conserving surgery, pN+

99200A 5-LRC 97% vs 91% p=0.01

Rouesse, de la Lande et al. IJROBP 2006 Toledano, Azria et al. JCO 2007

At the cost of increased acute and late toxicities

ARCOSEIN 5-LRC 97% vs 91% p=0.02

No. Stage ChT RT* pCR Epid. Grade 3 %

Formenti et al 35 T3-4 5FU-ci 50 Gy 20 26 IJROBP 1997 Preop 200mg/m2

%


RCC preop Ins9tut Curie S14

Phase II, 2001-‐2003, Unifocal breast cancers, 59 women

T2-‐3, N0-‐1, M0. not ini9ally amenable to breast-‐conserving surgery

Bollet, Sigal-Zafrani et al. Eur J Cancer, 2006

Age (ans)! Median 49 (31-65)!Menopausal! pre! 59%!cT! T2! 73%!cN! N0! 54%!Ellis-Elston! Grade 1-2! 75%!

FUN 1

FUN 2

FUN 3

FUN 4

RT

Inclusion workup

Preop. workup

MCA TCA RT

Pathological response and HR

No pCR 4 FEC100

HR+ TAM x 5 years

5FU pc 500 mg/m2 D1-D5 Vinorelbine IV 25 mg/m2 D1;D5 Breast, IMC, supra/infra-

clav 50 Gy / 25 f

Normal acute toxicity Normal compliance

No perop complication

I.Curie S14

•  Median 9me-‐lapse before surgery – Since end of RT 43 days (13-‐73) – Since biopsy 123 days (106-‐162)

•  69% (41 pa9ents) : breast-‐conserving •  31% (18 pa9ents) : mastectomy

•  + axillary lymph node dissec9on in all cases

Abcess in 8% (required surgery in 3%) Bollet, Sigal-Zafrani et al. Eur J Cancer, 2006

pathological Complete Response = 27%

RCC neoadjuvant Ins9tut Curie S14

RCC neoadjuvant Ins9tut Curie S14 How to evaluate the response?

= MRI, best method RECIST ≥ 50%

YES> 50% chance of pCR NO < 10% chance of pCR

Bollet, Thibault et al, Int J Radiation Onc Biol Phys 2007

RCC neoadjuvant Ins9tut Curie S14 Long-‐term Results

Bollet, Belin et al, Radiother Oncol 2012

@ 5 years : •  OS 88% [95% CI 80–97] •  LRC 90% [95% CI 82–98] •  LC 97% [95% CI 92–100]

Toxicity •  8% with ≥ 1 grade 3 (telangiectasia, fibrosis) •  31% with ≥ 1 grade 2 (telangiectasia, fibrosis, lymphoedema and dyspnea)

Cosmetic •  46% without (11%) or only minor modification (34%) •  11% deformed breast




Conclusion


S14 Phase II Trial A histological grade 3 was the only clinicopathological factor independently associated with pCR (p = 0.004)

Tumors which did not express FGFR1 protein on pretreatment biopsies were more resistant to chemoradiotherapy than those with FGFR1 expression

The FGFR1 tumoral expression was independent from the proliferative markers (histological grade and mitotic index), meaning that this gives us an additional information on the tumoral phenotype.

Massabeau, Sigal-Zafrani et al BCRT 2012

RCC neoadjuvant Ins9tut Curie S14 predic9ve factors of tumour response

RT in the preopera9ve secng predic9ve factors of late toxicity?

Rodningen R&O 2008

TGFβ Polymorphism

(SNP)

Kelsey IJROBP 2012

Radiation Induced CD8 Lymphocyte Apoptosis

RILA

Azria Lancet Oncol 2012




Conclusion


Vicini et al.IJROBP 2002

Op9misa9on of RT technique

Better dose homogeneity

Better Organs@Risk preservation

Alle Ding sind Gift und nichts ohn‘ Gift; allein die Dosis macht, das ein Ding kein Gift ist.

Everything is poison and nothing is poison; only

the dose makes the poison

Paracelsus said

Maybe it is time to bring down some dogma.

Duenas González JCO 2011

Low dose Gemcitabine CDDP Concomitantly with RT for cervical SCC

Op9misa9on of concomitant CT




Conclusion


Taxanes

232 Inflammatory Breast Cancer

Abrous-Anane et al, Bollet IJROBP 2010

Could RT replace surgery ader NA CT for early breast cancers?

Neoadjuvant therapy, compared with adjuvant therapy, was associated with a statistically significant increased risk of locoregional recurrence when radiotherapy without surgery was adopted

Mauri et al. JNCI 2005

Year of diagnosis

RT Surgery

165 pts with cCR after 4 cycles of NA CT: 100 RT, 65 surgery (12 mastectomies)

Larger tumours treated with RT Trend towards younger with RT

Ring et al JCO 2003 5-LR in the no surgery CR/US: only 8%.

Rousseau et al JCO 2006

FDG PET capability to predict pCR of NA CT was, after 2 courses, associated with a sensitivity, specificity, and negative predictive value of 89%, 95%, and 85%

What about now, with MRI, 18 FDG PET-scan?

Punglia NEJM 2007




Conclusion


Conclusions

. Is there a real contra-indication to a breast RT?

. Could pre-operative RT be called for?

Meeting early with the radiation oncologist could be of value in some cases

Different CT regimen are tested concurrently to RT to ameliorate therapeutic ratio (Taxanes, Vinorelbine…)

Interesting Neoadjuvant results, and non randomised data in rescue

Optimisation of radiotherapy techniques, and prediction of response to chemoradiotherapy are warranted

Chemoradiotherapy is an option for Inoperable breast Cancers under Neoadjuvant chemotherapy (≈2%), and Inflammatory breast cancers (> 5%)

Patients should be refered for surgery whenever possible in a M0 setting

Place et rôle du radiothérapeute dans le TNA Place of the radiotherapy in NA treatment

[email protected]


Merci ! תודה

Acute toxicity

! Rouesse! ! Arcosein!

! Seq! Conc! p! Seq! Conc! p!

Epidermitis! Grade ≥2 ! 21%! 29%! 0.03! Grade ≥1! 37%! 41%! NS!

Fever!Febrile

Neutropenia! <1! 1! 0.007! Fever! 5! 7! NS!

Cardiac! LVEF ↓15%! 2! 6! 0.02! Grade ≥1! 1! 1! NS!

Neutropenia! Grade ≥3! <1! 14! 0.0001! Grade ≥1! 36! 37! NS!

Esophagitis! Grade ≥1! 13! 17! 0.02!Rouesse, de la Lande et al. IJROBP 2006 Calais Cancer Radiothérapie 2004

(grade >=2)" Seq" Conc" p"Fibrosis" 5" 25" 0.003"Telangectasia" 7" 25" 0.001"Atrophy" 20" 44" 0.001"Hyperpigmentation" 15" 30" 0.02"Deformation" 14" 29" 0.002 "Pain" 12" 22" 0.07"Œdema" 0" 1" "Lymphoedema" 7" 5" "Toledano, Garaud et al. IJROBP 2006 Toledano, Bollet et al. IJROBP 2006

Late toxicity

Pourquoi associer RT et CT ?

1. Pas de retard entre initiation de la RT et de la CT 2. Potentialisation de la RT et augmentation du CLR 3. Diminution du temps de traitement global

NSABP : RT-CT conco = 0,5% RLR/an CT puis RT >1% RLR/an

Pourquoi ne pas associer RT et CT ?

1.  RT = risque d’impacter le capital médullaire et la dose intensité de la CT

2. Les CT (ex anthracycline) ne sont pas toutes compatibles de façon concomitante avec la RT 3. Augmentation des toxicités

Bénéfices et Risques théoriques

Kurtz Ann Oncol 1999

•  Retrospective study, 535 patients

•  109 RT-CT, 276 CT + RT, 106 RT + CT, 44 RT- CT « sandwich »

•  Facteurs pronostiques + péjoratifs dans le groupe conco

•  Control Local : Conco 92% vs Séquentiel 83% p<0,001

RCC neoadjuvant Ins9tut Curie S14 Tumours

Type histo.! CCI! 69%!

EE! Grade I! 22%!Grade II! 49%!Grade III! 25%!

CIC! Oui! 27%!HER2 +++! Oui! 17%!HR! HR+! 69%!


RCC neoadjuvant Ins9tut Curie S14 Acute Toxicity

% Grade 3 % Grade 4

Epidermite 14 -

Hématologique 24 22

Digestive 12 2

Cardiovasculaire 5* - * Les 3 patientes l’ont eu pendant leur premier cycle de ChT, avant le début de la radiothérapie


•  No per-‐op. or immediately post-‐op. complica9on

•  Median hospital stay 7 days (3-‐12)

•  5 abcesses –  2 with drainage

•  2 hematomas

•  34% lymphocele aspira9on

RCC neoadjuvant Ins9tut Curie S14 Post-‐op. Toxicity

RCC neoadjuvant Ins9tut Curie S14 compliance

•  Chemotherapy weekly dose-‐intensity

median (% theorical dose) –  5 Fluorouracil 98 61-‐112

–  Vinorelbine 98 50-‐105

•  Radiotherapy –  Median breast Dose (Gy) 50 46-‐52

–  Treatment interrup9on > 7 d 8%

Median 2 days 2-‐15

RCC neoadjuvant Ins9tut Curie S14 Results

No. %

Clinical Response

Complete 20 34

Partial 20 34

Stable 19 32

Breast-conserving surgery 41 69

pathological Complete Response* 16 27

Axillary Lymph Nodes

pN+ 26 44

pN- 33 56 * < 5% residual disease, without mitosis

« We believe that the only realistic benefit that one can expect using concurrent chemotherapy with radiotherapy is improvement in local control rates… »

« we must consider late toxicity after BCT as an important end- point in breast cancer clinical trials »

Adjuvant breast cancer treatment : The longer is not the better !

Toledano et al. Cancer Radiother 2008

Reflexion on treatment duration : The shroter seems to be better for patients, but …

. The ARCOSEIN « late toxicities and Cosmesis » evaluated population . 120 reassessed for depression . 8,1 years Follow Up . 6.7% with probable depression, and 12.5% with possible depression.

. Adjuvant Chemoradiotherpy : . Rational . 3 Phase III randomized trials . Late toxicities and cosmetic effects

. Neoadjuvant Chemoradiotherapy : . Breast Conservative treatment . Preoperative rescue

. Biological selection of patients candidats

PLAN

. Novel chemotherapies regimen (phase II trials)

« We believe that the only realistic benefit that one can expect using concurrent chemotherapy with radiotherapy is improvement in local control rates… »

« we must consider late toxicity after BCT as an important end- point in breast cancer clinical trials »

Adjuvant breast cancer treatment : The longer is not the better !

Toledano et al. Cancer Radiother 2008

Reflexion on treatment duration : The shroter seems to be better for patients, but …

. The ARCOSEIN « late toxicities and Cosmesis » evaluated population . 120 reassessed for depression . 8,1 years Follow Up . 6.7% with probable depression, and 12.5% with possible depression.

. Adjuvant Chemoradiotherpy : . Rational . 3 Phase III randomized trials . Late toxicities and cosmetic effects

. Neoadjuvant Chemoradiotherapy : . Breast Conservative treatment . Preoperative rescue

. Biological selection of patients candidats

PLAN

. Novel chemotherapies regimen (phase II trials)

No. Stage ChT RT* pCR Epid. Grade 3 %

Formenti et al 35 T3-4 5FU-ci 50 Gy 20 26 IJROBP 1997 Preop 200mg/m2

Formenti et al. 44 IIB-III Paclitaxel 45 Gy 16 7 JCO 2003 Preop

Kao et al. 16 IIIB-C VLB + P 60 Gy 46 50 IJROBP 2004 Preop or P * Breast + Lymph nodes

%

Could RT be part of the NA treatment? In associa9on with other regimens of CT?

Bollet et al. 59 IIB-III FU-N 50 Gy 27 17 EJC 2006 Preop

Bellon et al. IJROBP 2000

A retrospec9ve study of concurrent RT and taxanes (pacli or doce) in high risk BC

2-LC 74%, 2-OS 66%.

Weekly Docetaxel 20mg/m2 x2/week

Karasawa et al Breast Cancer 2003

CT (4 AC60) RT-CT (12 Paclitaxel weekly 60 mg/m2)

RT-CT (4 Paclitaxel 135-175 mg/m2/ 3 weeks) Surgery

Skin Toxicity (no G3-4) Lung Toxicity (P hebdo) RT interruption 25%

Burstein et al., IJROBP 2006

phase II trial

40 patients breast cancer stage II-III

RT (1.8 Gy/#) DT 39,6Gy (breast) 45Gy (chest wall)

Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible (…) Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury

A phase II trial of adjuvant concurrent RT and paclitaxel

CT (4 AC60) Surgery RT-CT (4Taxol 175 mg/m2/ 3 weeks)

Chen et al., IJROBP 2012

44 patients 39.6 Gy / 22# + 14 Gy / 7#

Median F-U > 6y The 5-DFS 88%, 5-OS 93%, 5-LC 100% No cases of radiation pneumonitis No significant change in the diffusing capacity for carbon monoxide either immediately after RT or with extended F-U. Acute Grade 3 skin toxicity in 2 pts. Late cosmesis was not adversely affected. Conclusions: excellent LC & well tolerated.

A phase II trial of concurrent RT and paclitaxel ader BCS in pN+ BC

CT (3 FEC100) RT-CT (9Docetaxel 35mg/m2/week)

Chow et al., Acta Oncol 2014

32 patients

45 Gy / 25# + (5.4Gy/3# or 9Gy/5#)

A phase II trial of concurrent RT and weekly docetaxel

Early close due to high rate of symptomatic radiation pneumonitis

17 (55%) symptomatic radiation pneumonitis (RP). 8 (25%) grade 3 pneumonitis 1 (3%) grade 5, died of acute respiratory distress syndrome associated with RP

Ismaili et al., BMC Res Notes 2010

6 cycles of (AC60, FAC50; FEC75) or CMF

After mastectomy or BCT, the adjuvant treatment based on RT and concurrent anthracycline CHT (vs CMF) reduced breast cancer relapse rate, and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. There were more hematologic and non hematologic toxicities in the anthracycline group

Concomitant adjuvant chemo-radiation therapy with anthracycline-based regimens in breast cancer: a single centre experience Livi L, Meattini I, Scotti V, Saieva C, Simontacchi G, Marrazzo L, Franzese C, Cassani S, Paiar F, Di Cataldo V, Nori J, Jose Sanchez L, Bianchi S, Cataliotti L, Biti G.

PURPOSE: This study was done to evaluate the toxicity related to concurrent radiotherapy and anthracycline (AC)-based chemotherapy in the adjuvant treatment of early breast cancer and to investigate the impact of treatment interruptions and the feasibility of this uncommon therapeutic approach .MATERIALS AND METHODS: From September 2002 to December 2007, 60 patients were treated at our Centre. The mean age at presentation was 48.5 (range 38-64) years. All patients underwent conservative surgery, and radiotherapy to the entire breast (mean dose 50 Gy; range 46-52 Gy). AC-based regimens consisted of four cycles of AC (doxorubicin plus cyclophosphamide) or four cycles of epirubicin (EPI) followed by four courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). RESULTS: Concomitant treatment caused acute skin G3 toxicity in 8.9% of patients and one case of G4 toxicity (1.7%). Concerning cardiac assessment, six of the 56 evaluable patients (10.7%) developed an asymptomatic decline of left ventricular ejection fraction >10% and <20% of the baseline value. Radiotherapy was temporarily stopped in 21.3% and chemotherapy in 57.1% of patients. CONCLUSIONS: In our experience, concomitant chemotherapy did not emerge as a significant factor in radiotherapy interruption. Moreover, no severe cardiac events were recorded.

Which Chemotherapy Regimen ?

5FU pc 500 mg/m2 J1 à J5 Vinorelbine IV 25 mg/m2 J1 et J5

RT – CT (4 FUN) à Surgery à 4 FEC 100

Phase II, 2001-2003

Unifocal breast cancers, T2-3, N0-1, M0.

Conservative surgery impossible

60 patients assessed, 59 evaluables

BCS was performed in 69% (n=41) patients !

« Progression of inoperable breast cancer under NACT is a rare event (less than 2%) for which XUN/FUN-based chemo-radiotherapy could be proposed as locoregional ‘‘rescue’’ therapy »

A feasibility study of neo-adjuvant low-dose fractionated radiotherapy with two different concurrent anthracycline-docetaxel schedules in stage IIA/B-IIIA breast cancer. Nardone L et al. Tumori. 2012 Jan-Feb;98(1):79-85.

AIMS AND BACKGROUND: The aim of the study was to evaluate the feasibility of neoadjuvant low-dose fractionated radiotherapy, in combination with two anthracycline-docetaxel regimens, in breast cancer treatment. MATERIALS AND METHODS: Women with stage IIA/B-IIIA breast cancer were assigned to receive the treatment of low-dose fractionated radiotherapy (0.4 Gy/per fraction, 2 fractions per day, for 2 days, every 21 days for 8-6 cycles) with concomitant neoadjuvant chemotherapy with non-pegylated liposomal doxorubicin and docetaxel. Two chemotherapy schedules were planned to be combined with low-dose fractionated radiotherapy. The first schedule consisted of four cycles of non-pegylated liposomal doxorubicin sequentially followed by four cycles of docetaxel, and the second schedule consisted of six cycles of non-pegylated liposomal doxorubicin plus concomitant docetaxel. Acute toxicity was evaluated according to the Radiation Therapy Oncology Group score system. Pathological response was evaluated by the Mandard score and expressed as tumor regression grade. RESULTS: Between March 2008 and February 2009, 10 patients underwent low-dose fractionated radiotherapy and concomitant chemotherapy. No grade 3-4 breast toxicity was observed. Five patients had a clinical complete response. Seven patients underwent conservative surgery. Overall, tumor regression grade 1 (absence of residual cancer) was achieved in one patient (10%) and grade 2 (residual isolated cells scattered through the fibrosis) in 4 patients (40%). The pathologic major response rate (tumor regression grade 1 + 2) was 20% in patients receiving low-dose fractionated radiotherapy and sequential non-pegylated liposomal doxorubicin and docetaxel and 80% in the group receiving low-dose fractionated radiotherapy and concurrent non-pegylated liposomal doxorubicin and docetaxel treatment. CONCLUSIONS: Concomitant low-dose fractionated radiotherapy combined with anthracycline and docetaxel is feasible. The toxicity profile of radio-chemotherapy was similar to that of chemotherapy alone: there was no acute skin or cardiac toxicity. The concurrent application of liposomal doxorubicin and docetaxel with low-dose fractionated radiation led to higher histological response rates compared to the sequential application of the same two drugs.

marc bollet : role of radiation oncologist in neoadjuvant breast cancer treatment

Health & Medicine

phase ii trials

phase ii trial

local control rates

cosmesis evaluated population

breast conservative treatment

na treatment marc

patients candidats plan

rt replace surgery