The rationale for concurrent chemotherapy and radiotherapy in small cell lung cancer

Dr Hannah Lord

Ninewells Dundee17th Sept 2010

Small Cell • 20% of all lung cancer• Associated with smoking• Rapid doubling time• Falling incidence in many parts of UK,

not in Scotland• A systemic disease, even when

staged as “localised.” As such, systemic treatment is vital.

The History• In 1969, 5 year survival:

1% with surgery4% with radiotherapy

• In 1970s, advent of platinum based chemotherapy.

• Led to 4-5 fold improvement in response rates

Small Cell

• With chemo, excellent responses, but early and frequent relapse.

• Need to build on the improvement.

XRT• XRT already well known as effective.• XRT potentiates the effect of

chemotherapy• XRT has non over-lapping toxicities

with chemotherapy• XRT has different mode of action and

may deal with potentially chemoresistant disease

Evidence For XRT

• 13 randomised controlled trials have investigated the role of XRT

• Pignon(1) 1992 meta-analysis (and Warde(2) 1993)

• 2103 patients with LD

• 433 had ED

1. Pignon JP et al, N Engl J Med 1992; 327:1618-1624 December 3, 19922. Warde P et al “Does thoracic irradiation improve survival and local control in limited stage small cell

carcinoma of the lung?” JCO 1992;10:890-895

• 3 year survival improved from 8.9% to 14.3%

(5% improvement)

• HR = 0.86 = 14% reduced risk of death

• No difference if LD / ED or timing of XRT

Role of XRT • Value of XRT proven.

• Principles of radiotherapy are to give the treatment in as short a time as possible for maximum effectiveness

• Minimise re-growth of tumour, which is known to have a rapid doubling time

XRT • Concurrent treatment:

i) To reduce overall treatment time (repopulation of tumour)

ii) To allow 2 modalities to potentiate one another

ii) ? to improve outcomes

How to determine timing of XRT?

• Randomised controlled trials• 8 looking at timing of XRT• 3 positive• 5 negative

Trial 1: NCIC study (3) 1993

• Randomised controlled trial in Canada

• 308 pts

• XRT commencing at cycle 2 (week 3) vs. cycle 6 (week 15)

• 40Gy in 15 fractions given

3. N Murray et al Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. JCO Vol 11 336-344, 1993 The National Cancer Institute of Canada Clinical Trials Group

NCIC ResultsEarly XRT Late XRT p Value

PFS 15.4 11.8 0.36

OS ( median)

21.2 16.0 0.008

3 year survival

30% 22% 0.008

5 year survival

26% 11% 0.008

Trial 2: Jeremic (4)

• Yugoslavian study 1997 • 107 patients• 4 x Carbo Etop and 4 x Cis Etop (carbo with XRT)• 54Gy in 1.5Gy / fraction given bd• XRT weeks 1-4 (early) or weeks 6-9 (late)

Early Late P valueMedian survival (months)

34 26 0.027

5 year survival (%)

30 15 0.027

4. Jeremic et al “Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study” JCO Vol 15, 893-900, 1997

Trials 3: Takada (5)

• Japanese study 2006

• 231 patients

• 4 x EP with 45Gy in 1.5Gy fractions given bd

• XRT started d2 cycle 1 vs. after cycle 4 ( sequential rather than late)

5. Takada M, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20: 3054-3060, 2002

Results

Concurrent SequentialMedian survival (months)

27.2 19.7

2 year survival (%) 54.4 35.1

3 year survival (%) 29.8 20.2

5 year survival (%) 23.7 18.3

P= 0.097 not significant due to small sample size

Costs of XRT

• Increased haematolgical toxicity• Similar oesophagitis ( 9% vs 4%)• 1% incraese in treatment related

deaths

• Well tolerated overall

Negative trials 1: Perry (6)

• US Study 1987• 399 patients: chemo, vs. chemo + early XRT, vs.

chemo + late XRT

• Results:

• XRT group as a whole did better that chemo alone group

• But no benefit from early vs delayed XRT6. Perry MC et al Chemotherapy with or without radiation therapy in limited small cell lung carcinoma of the lung NEJM 1987;316:912-918

Negative trials 2: Spiro• A London based trial (7) published 2005, replicated the

NCIC study.

• 3 cycles of CAV followed by 3 cycles of EP

• XRT with first course of EP (4th cycle of chemo) vs.

XRT with last course (6th) of chemo

• Failed to demonstrate a survival advantage from early XRT with chemo.

7. Spiro SG et al JCO Vol 24 No 24 2006: pp. 3823-3830 2006 Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis

Negative trials 3-5

• Work et al, James et al, Gregor et al, all negative.

• No advantage shown to early XRT

What do we do?

A meta-analysis!

Meta-analysis 2004 (6)

• Looked at 7 studies (Spiro not published at that time - 2006)

• 1524 patients

6. B. Fried et al Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for Limited-Stage Small-Cell Lung Cancer JCO Vol 22, No 23 , 2004: pp. 4837-4845 2004 American Society of Clinical Oncology.DOI: 10.1200/JCO.2004.01.178

Outcome In favour of early XRT

2 year survival

Relative risk

1.17 (CI = 1.02-1.35)

3 year survival

Relative risk

1.13 (CI = 1.13-0.92)

(not significant)

Meta-analysis Summary• A small but significant improvement

in 2-year OS for ERT versus LRT

• Similar to the benefit of adding RT to chemotherapy, or to addition or prophylactic cranial irradiation.

Cautions:• Studies using platinum-based chemotherapy had

2 year OS RRs of 1.30 (95% CI, 1.10 to 1.53; P 0.002) favouring early XRT.

3 year OS RRs of 1.35 (95% CI, 1.07 to 1.70; P 0.01)

BUT:

• Studies using once-daily fractionation showed no difference in 2- and 3-year OS for early vs. late XRT.

• Studies using non-platinum-based chemotherapy regimens had non-significant differences in OS.

• Next Step?

Cochrane Review • OS at 2 and 5 years:

not significantly different for early vs late XRT.

• However, if removed 1 trail, which did not use platinum,

survival advantage at 5 years for early vs. late OR = 0.64 p=0.02

• If XRT was given within < 30 days:

5 year survival was even better OR=0.56 p = 0.02

So……• Radiotherapy adds to chemotherapy

without doubt

• Early appears to be superior to late, but this is more evident when given with platinum based chemo, and if given in hyperfractionated manner (i.e. bd)

• Short overall treatment time is best

Future• Are you convinced? Or confused?

• bd fractionation ? Do we move to this? CONVERT study ongoing to clarify this question in UK and Europe

• Dose escalation – no proof that higher doses lead to better outcomes ( although common in N America - get paid / fraction)

Thank you and any Questions