What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?

From Cancer Guidelines Wiki

(Redirected from Clinical question:What is the clinical benefit of the addition of induction radiotherapy to induction chemotherapy in stage IIIA (N2) NSCLC?)

Jump to: navigation, search

Guideline contents > What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?

Information on authorship and revision

Guidelines commissioned by

Last modified:
21 November 2012 15:04:29

Author(s):

Dr Stephen Barnett — Author
Cancer Council Australia Lung Cancer Guidelines Working Party — Co-author

Cite this page

Dr Stephen Barnett. What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC? [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=47745, cited 2013 May 26]. Available from http://wiki.cancer.org.au/australia/Clinical_question:What_is_the_clinical_benefit_of_the_addition_of_neoadjuvant_radiotherapy_to_neoadjuvant_chemotherapy_in_stage_IIIA_(N2)_NSCLC%3F. In: Cancer Council Australia Lung Cancer Guidelines Working Party. Clinical practice guidelines for the treatment of lung cancer. Sydney: Cancer Council Australia. Available from: http://wiki.cancer.org.au/australia/Guidelines:Lung_cancer.

1 What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?
- 1.1 Introduction
2 Defining operable and inoperable disease in stage III
- 2.1 Randomised controlled trials of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy
3 Evidence summary and recommendations
4 References
5 Appendices

What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?

Introduction

Defining operable and inoperable disease in stage III

The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.

Read full explanation

Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.

The decision as to operability should be made in a multidisciplinary setting.

Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).

In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.

Neoadjuvant chemotherapy followed by surgical resection became a standard of care internationally in clinical N2 NSCLC^[1]^[2]^[3] based on the very poor survival of patients treated with surgery alone in this setting.^[4]^[5]^[6]^[7] Theoretical improvements in resectability, local control and subsequent survival with the addition of radiotherapy to neoadjuvant chemotherapy must be balanced against the potentially increased morbidity and mortality of surgery in this setting.

Back to top

Randomised controlled trials of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy

Girard et al (IFCT – 0101)^[8] randomised 46 patients with resectable cIIIA-N2 NSCLC in a phase II study with primary endpoint of feasibility. Response rate was significantly higher after neoadjuvant chemoradiotherapy versus chemotherapy alone (87% versus 57%, p = 0.049).

Despite two completed phase 3 studies published only in abstract form^[9]^[10] and a third well designed trial attempted by the RTOG and abandoned due to poor accrual^[11] only one phase 3 study (enrolling a majority of cIIIB patients) has ever been published.

Thomas et al^[12]^[13] randomised 558 patients with cIII (67% cIIIB) NSCLC between 1995 and 2003 at multiple German institutions, to:

three cycles of cisplatin and etoposide, followed by
twice-daily RT [45Gy] with concurrent carboplatin and vindesine, and then
surgical resection (and further RT [24Gy] if less than R0 resection)

versus

three cycles of cisplatin and etoposide, followed by
surgery, and
adjuvant radiotherapy (54Gy and further 24Gy if less than R0 resection).

On an intention to treat basis 37% versus 32% (NS) achieved complete resection. In those undergoing resection, complete resection was more often possible in the intervention group (75% versus 60% [p=0.008]). In patients with complete resection, mediastinal downstaging (46% versus 29% [p=0.02]) and pathological response (60% versus 20% [p<0.0001]) favoured the preoperative chemoradiation group.

Despite this evidence of improved loco-regional response, there was no difference in PFS (primary endpoint). Of interest, post operative mortality favoured the control group (5% versus 9% [p=0.11]), the trend being stronger after pneumonectomy (6% versus 14% [NS]), which was required in 35% in both arms.

Back to top

Evidence summary and recommendations

Evidence summary	Level	References
Neoadjuvant chemotherapy, with or without radiotherapy, is feasible.	III-1, II	^[8], ^[12], ^[13]
In patients with stage cIIIA (N2) NSCLC planned for surgery, preoperative chemoradiation compared to preoperative chemotherapy alone increases pathological response and mediastinal downstaging.	III-1, II	^[8], ^[12], ^[13]
In unselected patients with stage cIIIA (N2) NSCLC planned for surgery, preoperative chemoradiation compared to preoperative chemotherapy alone has not been shown to improve PFS or OS.	III-1, II	^[8], ^[12], ^[13]

Recommendation	Grade
In selected patients (excellent performance status and cardio respiratory reserve) with stage cIIIA (N2) NSCLC, planned for surgery that will entail less than pneumonectomy, it is reasonable to offer neoadjuvant chemoradiotherapy.	C

Practice point(s)
Surgery alone is not advised in cIIIA (N2) disease.

Instructions for commenting

- Statements regarding the inclusion/exclusion of issues should be clearly supported by scientific evidence, and specifically outline the relevance of the suggested material to the guidelines.

-If you have identified any gaps or errors in the content please suggest suitable text for inclusion.

- Use the blue 'Submit new evidence'-button to submit further/newly published evidence to be considered.

Already created a user account?

If you create a user account, your comments can be attributed to you and you also get alerts on any replies to your comments.

How to post a public comment

1) Use the blue 'Make a new comment' link below

2) Fill in the empty boxes

Warning: You need to fill out the subject line and box!

3) Press 'save page' to post your comment!

[History↑]

Make a new comment

Submission in regards to neoadjuvant chemoradiotherapy for stage 3A operable

In the 3A operable, the evidence (above) suggests that the addition of radiation to preop chemo has no impact on PFS or OS ( despite apparent pathologic response improvement) then the addition of radiation pre op has little significant impact at the expense of morbidity and potentially higher periop complications. I think the qualifier should be either preop chemotherapy alone or in highly selected patients preop chemoradiation.

125.255.80.146‎

There was no sig. improvement in overall survival. There was significant improvement in rates of complete resection, mediastinal down staging and pathological response all of which seem to correlate with survival in retrospective series. NB rates of complete resection on an intention to treat basis were not sig different and rates of complete resection were analysed in 'those undergoing resection' to arrive at the significant outcome, further rates of downstaging and pathological response were analysed 'in those undergoing complete resection'! Therefore I agree that there are limitations regarding acceptance of this as level 2 evidence supporting an advantage of the approach.

However neither is there an advantage of induction chemo therapy followed by surgery in terms of overall survival in this study. It's inclusion as the 'control arm' (implying it is a standard of care) is perhaps historic based on studies by Roth and Rossell. To be fair we do have more 'contemporary' evidence of feasability of the approach of induction CRT in the form of the intervention arm of INT139 and of the feasability of induction chemo therapy followed by surgery in the intervention arm of Van Meerbeck's EORTC trial.

In contrast, the 'downsides' of the induction CRT approach (ie higher complication rates post op) were not born out in a statistically significant manner either in the above study.

I would conclude with 2 further points:

1)'In selected patients (excellent performance status and cardio respiratory reserve)' may indeed be understood as you suggest to mean 'in highly selected patients' and

2) The recommendation includes 'is reasonable' and is grade 3.

I think the recommendation should stand, but would concede that your suggestion whilst having a different emphasis is not unreasonable ...... nor incompatible with the recommendation as stated.

Stephen.barnett‎

In the absence of a direct comparison between preop chemotherapy vs preop chemoradiation (apart from the complex Thomas trial which includes induction chemotherapy in both arms thus muddying the interpretation, plus the majority of patients had stage IIIB disease), I do not think we can say that it should be "chemotherapy alone or chemoradiation alone in highly selected patients". Why advocate using chemoradiotherapy at all if there is no difference in overall survival? For what it is worth,175 patients (30%) in the van Meerbeeck study died or progressed or had stable disease on chemotherapy alone and could not proceed to randomisation. This attrition is therefore not evident in the survival analysis. It is not clear in the Thomas study how many patients progressed during the induction phases and if there was a difference between preoperative chemotherapy vs chemoradiation. If progression is more likely with chemotherapy alone, would that affect the choice of the combination rather than the single modality? I agree, in the absence of better evidence, that the recommendation is reasonable as it stands.