49Radiotherapy dose fractionation Third edition
7.
Lung cancer
Background
Overall survival has increased in lung cancer in the past ten years, with the vast majority of
the gains occurring in disease stages I–III. There has been very little, if any improvement
seen in outcomes for stage IV patients.
1,2
Several publications have looked at access to
radiotherapy treatments (Level 2a).
3–5
Although many of these do not distinguish between
radical and palliative treatment, it appears that the proportion of lung cancer patients in the
UK accessing radiotherapy remains lower than expected.
Lung cancer staging has improved with routine use of positron emission tomography-
computed tomography (PET-CT) and endobronchial ultrasound (EBUS). Routine use
of intravenous (IV) contrast in planning has improved mediastinal target delineation.
Signicant technological advances have taken place in the delivery of radiotherapy. For
radical radiotherapy, four-dimensional computed tomography (4DCT) planning is replacing
three-dimensional conformal radiotherapy (3DCRT) as the standard of care. Bulky tumours
in certain anatomical locations, such as the paravertebral gutter, have improved dosimetry
with intensity-modulated radiotherapy (IMRT) and can more often meet normal tissue
constraints (NTC) than those planned conformally (Level 2c).
5–7
However, as with many
tumour types, there is insucient evidence to determine the ecacy of IMRT (Level 4).
5,7,8
Non-small cell lung cancer (NSCLC): curative therapy
Background
For patients with stage I and II lung cancer, anatomically based surgical resection remains
the treatment of choice. There is an emerging body of literature to support ablative
therapies in node-negative patients, of which stereotactic ablative radiotherapy (SABR)
has the most mature evidence base. There are, as yet, no completed randomised studies.
The two international randomised studies, which closed due to poor accrual, have been
published in pooled form (Level 2b).
5,9
There are a number of multi-institutional prospective
as well as retrospective series. Most concentrate on medically inoperable patients who are,
by denition, less well than their surgical counterparts. Published outcomes both in terms
of overall survival (OS) and disease-free survival (DFS) approach surgical series. Two-year
survival has been reported as 70% and ve-year survival 43%.
10,11
For medically inoperable patients with node negative tumours less than 5 centimetres (cm)
and in a favourable anatomical position, stereotactic ablative radiotherapy (SABR) is the
treatment of choice. The best outcomes occur when the tumour receives >100 Gray (Gy)
equivalent dose in 2 Gy per fraction EQD2 biologically equivalent dose (BED). Treatment
should be delivered with an interfraction interval of greater than 40 hours but less than four
days (Level 2a).
5,12
Stage III NSCLC is an extremely heterogeneous group in terms of tumour size and extent
of nodal involvement. Concurrent chemoradiotherapy has been demonstrated in meta-
analyses to give superior outcomes when compared with sequential chemoradiotherapy
or radiotherapy alone, but the optimum dose fractionation schedule has yet to be dened
(Level 1a).
5,13–15
Concurrent schedules have an increased incidence of grade three
oesophageal toxicities (Level 1b) and elderly patients with good performance status and
few co-morbidities derive as much benet from concurrent therapy as their younger
counterparts (Level 1b).
5,16
Although trimodality therapy remains an option, there is no evidence of benet over
denitive chemoradiotherapy. The only tumour group where there is some evidence to
support the use of trimodality therapy is Pancoast tumours (Level 1b).
5,17
There is no evidence of benet for chemotherapy delivered either neoadjuvantly or
adjuvantly to those receiving concurrent regimes (Level 1b).
5
50Radiotherapy dose fractionation Third edition
Dose escalation has been investigated in many studies. The recently published Radiation
Therapy Oncology Group (RTOG) 0617 trial did not demonstrate a survival benet in the
escalated arm. This trial has received signicant interest and review of individual data. The
quality assurance of the radiotherapy delivered may have been the cause of the lack of a
positive outcome so it is likely that this issue will be revisited (Level 1b).
5,18
For those unable to tolerate concurrent chemoradiotherapy, a sequential approach
demonstrates survival benet over radiotherapy alone.
15
The optimum therapy schedule
has yet to be dened (Level 1a).
5
Patients unt for systemic therapy should be treated with radiotherapy alone. Accelerated
fractionation schedules seem to improve outcomes (Level 1b) and can be safely combined
with concurrent and neoadjuvant approaches (Level 1b).
5,15,19–22
Recommendations
Medically inoperable T1–3 (≤5 cm) N0:
SABR using:
54 Gy in 3 fractions over 5–8 days (Grade B)
55 Gy in 5 fractions over 10–14 days (Grade B)
60 Gy in 5 fractions over 10–14 days (Grade B)
60 Gy in 8 fractions over 10–20 days (Grade B)
Medically inoperable stage I and II:
54 Gy in 36 fractions treating thrice daily over 12 consecutive days continuous,
hyperfractionated, accelerated radiotherapy (CHART) (Grade A)
55 Gy in 20 fractions (Grade C)
STAGE III:
Concurrent:
55 Gy in 20 fractions over 4 weeks with cisplatin and vinorelbine (Grade A)
60 Gy in 30 fractions over 6 weeks with cisplatin and etoposide (Grade A)
66 Gy in 33 fractions over 6.5 weeks with cisplatin and etoposide (Grade A)
Sequential:
55 Gy in 20 fractions over 4 weeks (Grade A)
60 Gy in 30 fractions over 6 weeks (Grade B)
66 Gy in 33 fractions over 6.5 weeks (Grade B)
54 Gy in 36 fractions treating thrice daily over 12 consecutive days (CHART) (Grade B)
Radiotherapy alone:
54 Gy in 36 fractions treating thrice daily over 12 consecutive days (CHART) (Grade A)
66 Gy in 33 fractions over 6.5 weeks (Grade A)
55Gy in 20 fractions over 4 weeks (Grade B)
Pancoast tumours (T3–4 N0–1):
45 Gy in 25 fractions over 5 weeks with cisplatin and etoposide followed by surgery
(Level 2b)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
51Radiotherapy dose fractionation Third edition
Non-small cell lung cancer (NSCLC): palliative radiotherapy
Background
The early trials were undertaken predominantly in patients unexposed to chemotherapy.
Current practice would see a signicant proportion of patients receiving sequential
chemoradiotherapy, with good performance status (PS) stage III patients managed with
radical concurrent chemoradiotherapy.
Overall the trials demonstrate that short-course radiotherapy can palliate intrathoracic
symptoms as well as long-course, but for those with good PS, higher doses confer a
moderate survival advantage at the expense of extra toxicity (Level 1a).
5,23
Recommendations
For those with good PS:
39 Gy in 13 fractions over 2.5 weeks with cord dose limited to 36 Gy (Grade A)
36 Gy in 12 fractions over 2.5 weeks (Grade A)
30 Gy in 10 fractions over 2 weeks (Grade A)
20 Gy in 5 fractions over 1 week (Grade A)
For those with poor PS:
17 Gy in 2 fractions over 8 days (Grade A)
10 Gy in 1 fractions (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
Small cell lung cancer (SCLC)
Background
The evidence base now favours integration of chemotherapy and radiotherapy at all disease
stages (Level 1a).
5
Concurrent chemoradiotherapy (stages I–III)
For patients with T1–4 and N0–3 SCLC, there is evidence for concurrent
chemoradiotherapy with radiotherapy starting no later than day one cycle three of
chemotherapy (Level 1a).
5,24
The UK-led phase III Concurrent Once-Daily Versus Twice Daily
Radiotherapy (CONVERT) trial has compared the internationally accepted standard of 45
Gy in 30 fractions treating twice daily over three weeks with 66 Gy in 33 daily fractions over
six weeks, nding no dierence between the two schedules.
25,26
In addition, a US intergroup
study is currently recruiting, which compares three fractionation schedules (45 Gy in 30
fractions treating twice daily; 70 Gy in 35 daily fractions and 61.2 Gy over ve weeks treating
once daily until day 21 and twice daily thereafter) (Level 1b).
5
One trial of early versus late concurrent thoracic radiotherapy used 40 Gy in 15 daily
fractions using a simple parallel opposed pair with cord shielding (Level 1b).
5,24
This can
shield the tumour and, in the modern era, cord constraints would be met using 3DCRT.
52Radiotherapy dose fractionation Third edition
Sequential chemoradiotherapy (stages I–III)
For those patients who, due to tumour size or co-morbidities, cannot be treated with
concurrent chemoradiotherapy, sequential chemoradiotherapy is the best alternative (Level
1a).
5
There is no denitive evidence to indicate the optimal schedule in this patient group,
although many use 40 Gy in 15 daily fractions (Level 2b).
5
Recommendations
Concurrent chemoradiotherapy with cisplatin and etoposide should be
delivered with either:
45 Gy in 30 fractions treating twice daily over 3 weeks (Grade A)
66 Gy in 33 fractions over 6.5 weeks (Grade A)
40 Gy in 15 fractions over 3 weeks (Grade B)
Sequential chemoradiotherapy:
40 Gy in 15 daily fractions over 3 weeks (Grade B)
50 Gy in 25 fractions over 5 weeks (Grade B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
SCLC: palliative thoracic radiotherapy
Background
A recent European Organisation for Research and Treatment of Cancer (EORTC) trial
randomised 498 patients with metastatic SCLC, who had not progressed during primary
chemotherapy to prophylactic cranial irradiation (PCI), with or without thoracic radiotherapy
with 30 Gy in ten daily fractions in addition. The trial did not meet its primary endpoint of
improved OS at one year, but OS at two years was in favour of mediastinal consolidation
(Level 1b).
5,27
Further data analysis has conrmed the OS and DFS benets are limited to
those with persistent intrathoracic disease (Level 1b).
5,28
Recommendation
Those patients with metastatic SCLC who respond to primary chemotherapy but
have persistent intrathoracic disease or thoracic symptoms should be considered for
thoracic consolidation radiotherapy with 30 Gy in 10 fractions over 2 weeks (Grade A).
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
53Radiotherapy dose fractionation Third edition
Prophylactic cranial irradiation (PCI) (stages I–III)
Meta-analysis of patients with stages I–III SCLC in complete or near complete thoracic
remission following primary chemoradiotherapy have an increased OS and decreased
incidence of intracerebral relapse when PCI is delivered (Level 1a).
5,29,30
25 Gy in ten fractions over 14 days carries the same disease relapse rate but lower mortality
when compared with 36 Gy in 18 fractions over 24 days (Level 1a).
5,30
Recommendations
Selected patients with locally advanced metastatic SCLC who respond to
primary chemotherapy should be oered PCI. Acceptable schedules are:
20 Gy in 5 fractions over 1 week (Grade A)
30 Gy in 10 fractions over 2 weeks (Grade A)
25 Gy in 10 fractions over 2 weeks (Grade A)
30 Gy in 12 fractions over 2.5 weeks (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
Prophylactic cranial irradiation (PCI) (stage IV)
Patients with stage IV SCLC who had any response to primary chemotherapy were
randomised to either PCI with one of ve schedules (20–30 Gy in 5–12 daily fractions) or no
PCI. The treatment arms had an increased OS and reduced symptomatic incidence of brain
metastases (Level 1b).
5
85% of patients were treated with either 30 Gy in ten fractions or 20
Gy in ve fractions. Two thirds received 20 Gy in ve fractions. The trial excluded patients
above 75 years of age.
31
Recommendations
Selected patients with metastatic SCLC who respond to primary chemotherapy
should be oered PCI. Acceptable schedules are:
20 Gy in 5 fractions over 1 week (Grade A)
30 Gy in 10 fractions over 2 weeks (Grade A)
25 Gy in 10 fractions over 2 weeks (Grade A)
30 Gy in 12 fractions over 2.5 weeks (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
54Radiotherapy dose fractionation Third edition
Mesothelioma
Background
The use of prophylactic irradiation of tracts of pleural interventions has been thought to
reduce the incidence of chest wall recurrence. Three small randomised studies have
been reported, one demonstrating benet, two not (Level 1b).
5,32–34
Currently in the UK, two
studies are addressing this issue. The Prophylactic Irradiation of Tracts (PIT) trial (closed
to recruitment in December 2015) randomises those with a visible scar following minor
pleural interventions between 21 Gy in three daily fractions using electrons or no treatment.
The Simultaneous Modulated Accelerated Radiation Therapy (SMART) trial randomised
those with larger pleural interventions between immediate radiotherapy with 21 Gy in
three daily fractions or treatment deferred until tract metastases occurred. The SMART
trial has been verbally presented (January 2016), with no benet of immediate radiotherapy
demonstrated.
35
For those patients with a diagnosis of mesothelioma and chest wall pain, controversy exists
about the utility of radiotherapy, especially where the pain is poorly localised. A recently
published non-randomised study demonstrates a 35% response rate when chest wall
radiotherapy is delivered to patients with localised pain (Level 2c).
5,36
Recommendation
Routine prophylactic irradiation of tracts is not recommended (Level 1b)
Selected patients with chest wall pain may benet from radiotherapy with either:
20 Gy in 5 fractions over 1 week (Grade C)
36 Gy in 6 fractions treating twice per week (Grade D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
5
55Radiotherapy dose fractionation Third edition
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