Treatment of LS (Stage I-III) SCLC · The Christie NHS Foundation Trust Treatment of LS (Stage...

The Christie NHS Foundation Trust

Treatment of LS(Stage I-III) SCLC

Prof C Faivre-Finn

Manchester Lung Cancer Group

Manchester Radiation Related Research Group

ESMO-The Christie Preceptorship programme on Lung Cancer

9th March 2018

@finn_corinne


DISCLOSURE OF INTEREST

I have no actual or potential conflict of interest in relation

to this presentation


Introduction

• Incidence of SCLC is declining-less than 10-15% of all

lung cancer cases Govindan JCO 2006

• Majority (> 95%) are associated with tobacco exposure

• One third present with stage I-III disease

• Excellent responses to CT and RT but few patients will

be long term survivors

• High risk of local relapse

• High risk of distant spread (brain)


How do we stage SCLC?

Veterans classification TNM classification

0 2 4 6 8

Survival (years)

0%

20%

40%

60%

80%

100%

IAIBIIAIIBIIIAIIIBIV

2621151213116

Median survival (months)

8008 patients

Role of PET controversial. Thomson. Lung cancer 2010

Limited stage = T1-4 N0-3 M0


• 76 year old male

• PMH HBP, mild COPD, ex smoker 30 PY

• PS1, MRC RS 1

• Presented with a cough and SOB on exertion

• FEV1 55% predicted, KCO 46% predicted

• Bronchoscopy-tumour obstructing the L main bronchus

• CT thorax&abdomenMass LUL

Station 4R, 4L, 5 and 7 lymph nodes

• CT brain clear

Stage I-III SCLC - Clinical case

Treatment options

• Sequential CTRT

• Concurrent CTRT

• Dose fractionation

– 40 Gy/15F

– 50-55 Gy/20F

– >60 Gy/30+F

• 3DRT or IMRT?

• PCI?


• Cisplatin is the best radiosensitiser and has higher RR�Cisplatin plays a major role in the treatment of LS-SCLC

• Cisplatin-Etoposide can be delivered at full dose with thoracic RT with an acceptable toxicity profile

• No change in systemic therapy in last 20 years

� No role for anthracyclines/pemetrexed/irinotecan

� No role for chemotherapy dose intensification

� No role for targeted agents

Systemic treatment in stage I-III SCLC


RadiotherapyCurrent evidence in stage I-III SCLC

• CTRT >CT (Pignon, Warde)

• Early RT >late RT (Fried , Cochrane review)

• Concurrent CTRT >sequential CTRT (Takada)

• Best survival results achieved with early BD concurrent CTRT(Turrisi, Jeremic, Faivre-Finn)

• PCI improves survival - 6% @ 3 years (Auperin)


Role of thoracic radiotherapyMeta-analyses

• Pignon et al. N Engl J Med 1992

� 13 randomised trials

� 2140 patients

� 3 year survival

� 8.9 % CT alone

� 14.3% CT+RT

� Thoracic RT benefited more younger patients

RR of death in the CTRT as compared with CT group

� 0.72 for patients <55 years old (0.56-0.93)

� 1.07 (0.70-1.64) for patients over 70

• Warde et al. JCO 1992

• Limitations of the metaanalyses• Response to treatment assessed on CXR

• Dated RT techniques (2D)

14% reduction in risk of death, p = 0.001


Timing of thoracic RT with chemotherapy

7 RCTsAdvantage of early (<9 weeks) radiotherapy

2 yr % NNT for benefit p

All (1524)

Platinum

Platinum+HART

+5.2 [0.6-9.7] 20 0.03

+9.8 [3.8-15.9] 10 0.001

+16.7 [9.4-26] 6 0.001

Fried et al. J Clin Oncol 2004


SER CONCEPT

EVEN BETTER

D1 D22 D43 D64

De Ruysscher et al. J Clin Oncol 2006

• SER most important predictor of

outcome

• When cisplatin based regimen are

used the ideal SER is < 30 days

• Supports the use of RT regimen • given concurrently with the first cycle of chemotherapy

• administered twice-daily

1 2 3 4

BAD

BETTER

OPTIMAL

EVEN BETTER


Japan Clinical Oncology GroupConcurrent vs. sequential CTRT

n=231

Concurrent

4 weekly PE

Sequential

3 weekly PE

RT (45 Gy BD) Day 2 Post cycle 4

CR (%) 40 27

MST (months) 27 19

5 yr survival (%) 24 18

Takada et al. J Clin Oncol 2002

(p =0. 097)


Standard of care for LS-SCLCIntergroup 0096

Turrisi et al. N Engl J Med 1999

Once daily Thoracic Irradiation

D1 D3

RT 45Gy/33D/25F

Twice daily Thoracic Irradiation

RT 45Gy/19D/30F

Lim

ited

Sta

ge S

mall C

ell

Lu

ng

Can

cer

CR→→→→PCI

If<CR

→→→→ No PCI

Registration

Randomisation

Restage

Chemotherapy (PE)

Radiotherapy

D22 D24 D43 D45 D64 D66

D1 D3 D22 D24 D43 D45 D64 D66

5 yr survival

26% BD vs 16 % OD


Utilization of Hyperfractionated Radiation in SCLC and Its Impact on Survival

• National Cancer Database.1999-2012

• 25,045 patients diagnosed with non-

metastatic SCLC (22,626 had survival

data)

• The utilization of BD radiation overall was 11.3%

• Treatment at an academic centre was

associated with a higher likelihood of

receiving BD treatment (OR: 2.29, p <

0.001).

• Median survival was 22.1, 17.2, 18.3,

19.2, and 19.5 months for patients

receiving 45 Gy BD, 45 Gy OD , 46-

59.4 Gy OD, 60-61.2 Gy OD , and 62 -

72 Gy OD (p < 0.001 for pairwise

comparison to BD)

Schreiber. JTO 2015


CTRT in the elderly

Subset analysis of Intergroup 0096

381 patients treated with BD vs OD CTRT

PS 0-1

age 30-82

31% ≥ 65 and 13% ≥ 70 years

Study not stratified per age groups

• Compliance to 4 cycles: 78% vs 90% for younger patients

• Toxicity (>70 vs. younger patients)• More severe hematologic toxicity (grade 4–5: 61% vs. 84%; p <0.01)

• More fatal toxicities (1% vs. 10%; p<0.01)

• No differences in non-hematologic toxicities

• Outcome according to age • No difference in event free survival rate, time to local failure, and duration of response

• Overall survival rates favored those younger than 70 years

(5 year 22% vs. 16%; p = 0.05)

Yuen et al. Cancer 2000

Once daily Thoracic Irradiation

D1 D3 D22 D24 D43 D45 D64 D66

RT 45Gy/33D/25F

Twice daily Thoracic Irradiation

D1 D3 D22 D24 D43 D45 D64 D66

RT 45Gy/19D/30F

Lim

ited

Sta

ge S

mall C

ell

Lu

ng

Can

cer

CR→→→→PCI

If<CR

→→→→NoPCI

RegistrationRandomisation

Restage

Chemotherapy (PE)

Radiotherapy


How can we improve survival rates further with radiotherapy?


Considerations for radiotherapy techniques

Modern techniques• 3D CRT/IMRT

• 4DCT and PETCT for RT planning

• IGRT

Better local control = Improved survival

Impact of advanced RT on outcome?


Intensity modulated radiotherapy

V20 33.1%MLD 19.4GyMax SC 47.9 Gy

V20 35%MLD 20.1 GyMax SC 35.3 Gy

IMRT modulates the intensity profile of the radiation delivered to the

patient allowing improved targeting of the radiation dose


3DCRT vs IMRT for stage I-III SCLC

• 223 patients treated at the MD Anderson between 2000-09 were retrospectively reviewed

• 119 receiving 3DCRT and 104 receiving IMRT

• Median age was 64 years (range 39-90 years)

• Radiation modality was not associated with differences in OS or DFS in either multivariable or propensity score-matched analyses

Shirvani. Int J Rad Oncol Biol Phys 2013


CONVERT multinational, phase III randomised study

RT 45Gy/30F/19D

Lim

ited

Sta

ge S

mall C

ell

SD,PR,CR→→→→PCI

If<SD→→→→ no PCI

Registration

Randomisation

RestageChemotherapy

Radiotherapy

D1 D3 D22 D24 D43 D45 D64 D66

Twice-daily (BD) thoracic RT

D1 D3 D22 D24 D43 D45 D64 D66

RT 66Gy/33F/45D

Once-daily (OD) thoracic RT

Stratification factorsCentreNo. of cycles chemo: 4 vs.6 PS: 0,1 vs. 2

RTP after randomisationRT started on D22 cycle 13DCRT or IMRTNo ENIQA programme

Chemotherapy4 to 6 cycles Cisplatin 25mg/m2 D1-3 or75mg/m2 D1Etoposide 100mg/m2 D1-3

547 patients

8 countries

75 centres

PS 0-2

No age limit


Overall survival

Median follow-up: 45 months

Overall survival(n=543)

BD OD Log-rank

Median(months)

30 (24-34) 25 (21-31)

p=0.14

1-year 83% (78-87) 76% (71-81)

2-year 56% (50-62) 51% (45-57)

3-year 43% (37-49) 39% (33-45)

5-year 34% (27-41) 31% (25-37)

Primary objective-overall survival Trial hypothesis

Expected survival BD arm 44%Projected survival OD arm 56%

(5) (1) (17) (30) (22) (13) (3)(3) (1) (27) (29) (25) (19) (3)

HR=1.18 with 95% CI 0.95-1.45 p=0.14

0

20

40

60

80

100

Aliv

e (

%)

273 224 151 92 54 25 6 2BD270 202 134 88 46 21 7 3OD

Number at risk

0 1 2 3 4 5 6 7Years from randomisation

OD

BD

Overall survival

Faivre-Finn. Lancet Oncol 2017


Acute Toxicity

•1 patient in each arm not assessable for oesophagitis, 6 patients for pneumonitis

•*1 patient in BD arm and 2 patients in OD arm (1 received sequential CTRT) died

from radiation pneumonitis

Organ at risk Arm N Median (Range)

Lung V5 (%) BDOD

246234

56.2 (7.2-88.5)60.8 (7.0-91.6)

Lung V20 (%) BDOD

252240

23.2 (0.1-35.4)28.8 (8.0-40.5)

Heart (% total dose)

BDOD

240229

2.0 (0-45.3)1.4 (0-36.2)

Spinal cord (max dose, Gy)

BDOD

251241

32.0 (1.3-45.8)41.7 (1.3-52.6)

Oesophagus (max dose, Gy)

BDOD

248236

45.7 (0.7-64.4)65.9 (2.2-71.7)

Oesophagus V35 (%)

BDOD

246230

34.0 (0-76.5)38.8 (0-82.8)

ARM BD (n=254) OD (n=256) p

AE (grade) 1-2

n (%)

3

n (%)

4

n (%)

5

n (%)

1-2

n (%)

3

n (%)

4

n (%)

5

n (%)

Oesophagitis 159

(62·6)

46

(18·1)

1

(0·4)

- 135

(52·7)

47

(18·4)

- - 0·85

Pneumonitis 51

(20·1)

3

(1·2)

1

(0·4)

1

(0·4)*

49

(19·1)

3

(1·2)

1

(0·4)

2

(0·8)*

0·70



Symptom Arm 0 1-2 3 4 p0,1,2vs 3,4

Dermatitis BDOD

233 (94.0)216 (92.7)

15 (6.0)17 (7.3)

- - -

Oesophagitis BDOD

219 (88.3)191 (81.6)

29 (11.7)39 (16.7)

-4 (1.7)

-0.06

Oesophagealstricture/fistula

BDOD

240 (91.8)226 (97.0)

8 (3.2)6 (2.6)

-1 (0.4)

-0.48

Pulmonaryfibrosis

BDOD

125 (50.6)120 (52.6)

119 (48.2)106 (46.5)

3 (1.2)2 (0.9)

-1.00

Pneumonitis BDOD

171 (69.0)154 (67.0)

71 (28.6)70 (30.4)

5 (2.0)5 (2.2)

1 (0.4)1 (0.4) 0.90

Myelitis BDOD

247 (99.6)223 (96.5)

1 (0.4)*8 (3.5)*

- - -

Other BDOD

92 (37.4)99 (42.7)

131 (53.3)113 (48.7)

20 (8.1)18 (7.8)

3 (1.2)2 (0.9) 0.78

•* Myelitis all grade 1

•@finn_corinne

Late Toxicity


CONVERT- CTC - Multivariate AnalysisAt-Risk Group PFS OS

Models Positive Negative P HR 95% CI P HR 95% CI

With 2-CTCs threshold

2 CTCs at baseline ≥ 2 < 2 0.021 1.85 1.10 to 3.12 0.006 2.15 1.25 to 3.70

ECOG PS 1 0 0.011 2.20 1.19 to 4.07 0.009 2.39 1.25 to 4.60

2 0 0.184 2.15 0.70 to 6.63 0.148 2.32 0.74 to 7.29


15 CTCs at baseline

≥ 15 < 15 <.001 6.03 3.00 to 12.08 <.001 6.19 3.08 to 12.42

ECOG PS 1 0 0.157 1.60 0.84 to 3.05 0.168 1.63 0.81 to 3.25

2 0 0.439 1.58 0.50 to 5.03 0.223 2.05 0.64 to 6.56


50 CTCs at baseline

≥ 50 < 50 0.002 3.59 1.58 to 8.18 0.003 3.42 1.52 to 7.67

ECOG PS 1 0 0.034 1.96 1.05 to 3.65 0.034 2.05 1.05 to 3.97

2 0 0.298 1.85 0.58 to 5.89 0.148 2.35 0.74 to 7.47

• CTC count is highly prognostic for survival

• Independent from other clinical factors (eg PET staging)

•15 CTCs predicted ≤ 2 years survival in 100% and ≤ 1

year survival in 70% of the patients

• Provides a hypothesis to stratify patients prospectively for

CTC count in future clinical trials

Fernandez-Guiterrez. World Lung 2016


Conclusions

• Radiation-related toxicities were lower than expected likely due to the use of modern RT techniques

• Survival in both arms was higher than previously reported

• BUT OD RT did not result in a superior survival or worse toxicity than BD RT

• 45Gy in 30 # BD should continue to be regarded as standard of care because

• CONVERT is not an equivalence trial

• However OD RT (66 Gy in 33 fractions) can be considered an alternative regime BD RT cannot be delivered


Practice defining trial


Intergroup studyCALGB 30610-RTOG 0538

Limited

SCLC

45 Gy BID/

3 weeks

61.2 Gy CB/

5 weeks

70 Gy QD/

7 weeks

45 Gy BID/

3 weeks

Experimental TRT arm

PS 0-1

PE X 4 → PCI

Cycle 1 or 2 TRT

Re-assess

VS.

Primary endpoints = OS


Can we improve survival rates further with systemic treatment?


SCLC and targeted agentsStudy Target Agent Design Result

NCI-C/EORTC

BAYER

MMP Marimastat

BAY 12-9566

+/- Maintenance

+/- Maintenance

Negative

Negative

ECOGCALGBHOG

VEGF BEV (B) Chemo + BChemo + BChemo + B

PositiveNegativeNegative

LLCG Vascular stabilizer

Thalidomide Chemo +/- T Negative

NCI-C VEGFR TKi ZD 6474 +/- Maintenance Negative

SWOG VEGFR TKi Sorafenib Monotherapy Negative

NCI VEGFR TKi ZD 2171 Monotherapy Negative

Rudin Bcl-2 Oblimersen Chemo +/- Negative

Langer Bcl-2 Obatoclax Chemo +/- Negative

ECOG mTOR CCI-779 +/- Maintenance Negative

HOG EGFR gefitinib Monotherapy Negative

JohnsonKrugDy

Kit Imatinib MonotherapyMonotherapyMonotherapy

NegativeNegativeNegative

EORTC GD-3 BEC2/BCG +/- Maintenance Negative

SWOG Proteosome Bortezomib Monotherapy Negative

SWOG RAS/VEGF Sorafenib Monotherapy Negative


Targeted agents and RT

Spigel et al. J Clin Oncol 2010

Phase II -29 LS-SCLC patients recruited

Early trial closure

Two patients developed tracheoesophageal fistulae

One patient died from an aerodigestive hemorrhage


Chemo-Radiotherapy:

cis-/carboplatin + etoposide

4 cycles

Biomaterial for translationalresearch:

Consolidation vs observation:

induction maintenance

max 1 year

combination nivolumab

nivolumab/ipilimumab

observation

Screening:

LD SCLCPCI

Tumour

evaluation:

PD

off

Voluntaryre-biopsy:

? FFPE block

yes

noR

•••• •••• ••••

3 6 9 3 6 9 1812

after randomisation

RT (Thoracic Radiotherapy): CT scans for tumourassessment

accelerated schedule preferred - up to 18 months: every 9 weeks

start: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks

day 1 of chemo cycle 2 - years 3 & 4: every 6 months

- at 5 years

0Week

Serum

At progression:

Whole blood Whole bloodWhole blood

RT

RT

from startof chemotherapy

-2

CT

Serum SerumSerum

FDG-PET-CT

or CT

Brain MRI

or CT

Biopsy:

FFPE block

or slides

27

CT •••• •••• ••••

14 16

STIMULI


Progress in stage I-III SCLC

SWO

G 9

713

SWO

G 0

222

NC

CTG

892

052

CA

LGB

923

5R

TOG

960

9EC

OG

259

6IN

T0096

QD

INT00

96B

ID

CO

NVER

T QD

CO

NVER

T BID

0

10

20

30

40

Me

dia

n S

urv

iva

l (m

on

ths

)

CT alone

Seq CTRT

ConCTRT

BD CTRT

CONVERT BD

5 year survival (%)

<10

10-15

20-25

25

34


Surgery for very limited SCLC?


Facts

• Stage I SCLC is diagnosed in ~5% of patients

• Paucity of prospective evidence in very early stage SCLC

• Staging, surgery and RT techniques have evolved dramatically in last decade


Surgery vs RT

MRC trial. 144 patients with ‘no evidence of metastatic disease, operable and fit enough for resection’

Surgery . ‘Patients allocated to surgery were to undergo thoracotomy with the

intention of performing a total resection of all growth’

Radical radiotherapy. ‘Patients allocated to radical RT were to be treated by the

technique customarily used by the radiotherapists’ (11% pall RT, 4% no RT)

R

Fox et al. Lancet 1973 No chemotherapy, no details on TNM


Surgery vs RT

Lad et al. Chest 1994

50 Gy/25#

Actuarial 2 year survival 20%

ECOG-EORTC 328 pts registered, 146 pts randomised, 13 pts stage I


NCI recommendationsRole of surgery

• The role of surgery in the management of patients with SCLC is unproven

• Evidence:

� Small case series and population studies have reported favourable outcomes for the minority of LD patients with very limited disease (level of evidence 3)

� A randomized study evaluating the role of surgery in addition to CTRT found no OS benefit with the addition of pulmonary resection [Lad et al] (level of evidence 1)

• Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and riskfrom the surgical procedure

http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung


Early

Locally-advanced

p=0.001

EarlyLocally-

advanced

Log

rank

Median 50 months95%CI 35,-

25 months95% CI 21, 29

p=0.0011-year 83% 79%

2-year 64% 50%

513 patients eligible for this sub-group analysis and 87 (17%) had early disease:

• 4 patients (4.6%) �� TNM stage I

• 83 patient (95.4%) �� TNM stage II

Toxicity

(number evaluated early/ locally-advanced)

Grade Early Locally-advanced

Chi-sq

(p-value)

Oesophagitis

(82/ 393)

0

1-2

≥3

32 (39%)

41 (50%)

9 (11%)

72 (18.3%)

237 (60.3%)

84 (21.4%)<0.005

Pneumonitis

(82/ 389)

0

1-2

≥3

59 (72%)

21 (25.6%)

2 (2.4%)

307 (78.9%)

74 (19%)

8 (2.1%) 0.52

CONVERT EARLY STAGE


SUMMARY

• For clinical guidelines : ESMO Ann Oncol 2010, 2013

NCCN Thorax 2016

NCI recommendations

• Cisplatin etoposide is still standard in combination with RT

• Progress has been made with RT!! We should all CONVERT to BDRT

• Role of surgery for stage I-II SCLC not well defined

• We need to increase our understanding of the biology and individualise treatment

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