Download Role of Radiation in Lung Cancer

Role of Radiation in Lung
Cancer
Eyad Alsaeed MD , FRCPC
Consultant Radiation Oncology
Prince Sultan Hematology Oncology Center
KFMC
Epidemiology
Cancer is a leading cause of death
worldwide: it accounted for 7.9 million
deaths (around 13% of all deaths) in
2007
making it the number one cancer killer
in both men and women worldwide.
Exceeding the combined
mortality
of breast , ovarian , cervical
cancer for women.
Prostate cancer for men.
IN
KSA
In 2002 lung and bronchial cancer were
the third leading cause of death in
men .
tenth leading cause of death in women.
Cancer Incidence for Most Common Sites (2004)
Cancer
Male
Female All
%
Breast
15
783
798
11.5
CRC
366
281
647
9.3
NHL
332
224
556
8.0
Leukemia
241
194
435
6.2
Thyroid
87
328
415
6.0
Liver
231
93
324
4.6
Lung
233
63
296
4.2
HD
166
98
264
3.8
Skin
136
125
261
3.7
Brain, CNS
147
100
247
3.5
Prostate
214
-
214
3.1
Stomach
141
70
211
3.0
Bladder
160
41
201
2.9
Uterus
-
117
117
1.7
Ovaries
-
108
108
1.5
All Others
1009
866
1875
26.9
Total
3478
3491
6960
100
Risk Factors
 Cigarette
responsible about
80% of lung cancer&100%
SCLC
 Radon gas the second cause
Lung cancer occupational
exposure
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Asbestos
Nickel
Chromium
Arsenic
Radon
naturally occurring inert gas & decay product of Uranium-238
particularly found in stone houses daughter products emit particles, delivering radiation to depth = 41-71 m RR 1.3-1.8
7

Since 1970 the prevalence of smoking
has increased in Saudi Arabia, as in
the rest of the world, and this will
likely lead to a lung cancer epidemic in
the coming decades
Presenting Symptoms
1.Local
cough, Dyspnea , hemoptysis, pleuritic pain
2.Nodal
recurrent laryngeal/ phrenic, SVCO, esophageal
compression
3.Distant
bony pains, brain mets
4. Nonspecific, initial symptoms such as weight
loss, weakness, anorexia, and malaise
5.Paraneoplastic
LUNG CANCER
paraneoplastic syndromes: (2%)
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Hypercalcemia (ectopic

parathyroid hormone,more
common in SCC,mental status
changes, hypotension
Cushing's Syndrome (2% of
SCLC,ectopic ACTH
secretion,HTN,hirsutism,moon
face,buffalo hump,truncal
obesity,thin skin,bruising,
abdominal striae.poor prognosis
SIADH (10% of SCLC.ectopic 
ADH secretion. hyponatremia. 
Seizures) not affect the

prognosis

Eaton-Lambert Syndrome
(impaired release of
acetylcholine ,muscle strength
improves with repetitive
movement,SCLC
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

Pulmonary Hypertrophic
Osteoarthropathy (common in
Adenoca, periosteal inflammation
causing bone and joint pain (usually in
knees or ankles), tibial tenderness,digit
clubbing, elevating alk phos,x-ray -periosteal inflammation and
elevation,bone scan -- intense
generalized increased uptake, especially
in long bones
Peripheral Neuropathy
Polymyositis
Dermatomyositis
Digit Clubbing
DIC
VIPOMA (flushing, diarrhea,
hypotension = carcinoid syndrome
Gynecomastia 2% of SCLC
INVESTIGATION
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1- Sputum cytology
( 3 samples , can diagnos central lesion 80%)
< 20% in small peripheral lesion
2- FNA : 90% accuracy
3-CT chest , abdomen ( s/s 70%)
MRI( if CT reveal uncerain medistinal or vertebral)
4- Bronchoscopy
5- Mediastinoscopy
6- VAT
7- Staging work up (brain , bone)
PFT for Radical RT
Consensus conference in Cambridge:
 FEV1 ≥ 40%
 FVC
≥ 45%
 DLCO ≥ 45%
 pO2 ≥ 60 mmHg
 pCO2 < 50mmHG
 O2 sat. ≥ 90%

12
contraindications to curative large field RT
– pt on home O2 with such poor pulmonary function from benign lung dz
that life
expectancy is < 6 mo
7/7/2017
Prognostic Factors

Most important are PS, extent, and
weight loss.
Host:

PS, weight loss*, sex

Tumor

Histo: no difference for advanced disease.
extent
Treatment:
operability, radiation dose, high dose cisplatinum.
PATHOLOGY
WHO Classification
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I. Benign
II. Dysplasia and CIS
III. Malignant
1. Squamous cell carcinoma 30%
– and spindle cell carcinoma

2. Small cell carcinoma 18%
– 1.Oat cell

3.Combined cell
3. Adenocarcinoma 40%
– 1.Acinar

2.Intermediate cell
2.Papillary
3.Bronchoalveolar 4.Mucus secreting
4. Large cell carcinoma 15%
– 1.Giant cell
2.Clear cell

Others
5. Combined epidermoid + adenocarcinoma
6. Carcinoid
7. Bronchial gland (cylindroma, mucoepidermoid, others)
8. Papillary tumors of surface epithelium
9. Mixed tumors and carcinomas (carcinosarcomas, etc.)
10. Sarcomas
11. Unclassified
12. Mesotheliomas (A.localized, B.diffuse)

Up to 45% contain 2 histologic patterns.
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SCLC STAGING
LIMITED DISEASE
30%
EXTENSIVE DISEASE
70%
SCLC: Staging
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Limited disease (LD)
– Confined to one hemithorax and regional
lymph nodes, including ipsilateral
supraclavicular lymph nodes
Extensive disease (ED)
– Extends beyond one hemithorax or involves
contralateral mediastinal, hilar, or
supraclavicular lymph nodes, and/or pleural
effusion with positive cytology
Ihde et al. In: DeVita et al, eds. Cancer: Principles & Practice of Oncology. 5th ed.
Lippincott-Raven; 1997:911-949.
SCLC Stage Distribution at Diagnosis
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LD: approximately 30–40% of patients . Most patients
with 2-year disease-free survival come from this group
ED: approximately 60–70% of patients.
Common sites of metastasis include:
– Bone, 19–38%
– Liver, 17–34%
– Bone marrow, 17–23%
– Brain, 0–14%
– Lymph nodes, 7–25%
– Soft tissue, 3–11%
SCLC Stage Distribution at Diagnosis:
1989–1996
80
Percentage of Patients
70
60
64%
62%
61%
50
Localized
Regional
Distant
Unstaged
40
30
20
18%
10
13%
7%
20%
17%
7%
12%
13%
6%
0
Total
Males
Females
Data from Ries et al, eds. SEER Cancer Statistics Review, 1973-1997. National Cancer
Institute; 2000.
Importance of XRT in SCLC
Chemotherapy vs Chemotherapy + RT
• JP Pignon, et al. NEJM. 327:1618-1624, 1992. - meta-analysis
– 2,103 pt with limited stage SCLC from 13 randomized trials comparing chemo
alone to chemo + RT
– end-point: survival
– RR of death with addition of RT = 0.86
– administration of thoracic RT produced a 14% reduction in the mortality rate
– conclusions :
• (1) limited stage SCLC, addition of thoracic RT produced a 14% reduction in
mortality rate, corresponding to a 5% greater 3-yr survival
• (2)benefit of radiation was greatest in pt < 55 yr
3-yr OS rate
pt age
chemo alone
chemo + RT
all pt
10%
15%
< 55 yr
9%
17%
> 70 yr
10%
9%
Importance of XRT in SCLC
Chemotherapy vs Chemotherapy + RT
not only survival but also Local control
• P Warde, et al. J Clin Onc. 10:890-895, 1992. - meta-analysis
chemo
chemo + RT
2-yr LR rate
77%
52%
2-yr OS rate
16%
23%
−1,911 pt with limited stage SCLC from 11 randomized trials
−end-points: survival, loco-regional control, toxicity
−odds of surviving 2 yr with RT vs without RT = 1.53
−overall increase in 2-yr survival = 5.4% (p<0.05)
−odds of thoracic failure at 2 yr with RT vs without RT = 3.02
−overall increase in 2-yr thoracic control = 25.3% (p<0.05)
−conclusions :addition of thoracic RT to chemotherapy produces a modest
improvement in survival and a large improvement in intrathoracic control in pts with
limited stage SCLC
20
Common Treatment Approach
Extensive Disease
Standard regimens for SCLC are considered to
be CAV or EP, or CAV/EP alternating regimen.
+
Prophylactic Cranial Irradiation
Limited Disease
Same chemotherapy
+
Concurrent Thoracic Radiotherapy
+
Prophylactic Cranial Irradiation
Timing of Chemo/RT
1- N Murray, et al. J Clin Onc. 11:336-344, 1993. - NCI
RCT
RT - 2nd cycle (n=155)
RT - 6th cycle (n=153)
p-value
CR rate
64%
56%
NS
median PFS
15 mo
12 mo
0.036
3-yr PFS rate
26%
19%
0.036
median survival
21 mo
16 mo
0.008
3-yr OS rate
30%
21%
0.006
5-yr OS rate
20%
11%
0.006
3-yr LR rate
>50%
>50%
NS
randomization:
(1) early RT = radiation given
concurrently with 2nd cycle of
chemotherapy
(2) late RT = radiation given concurrently
with 6th cycle of chemotherapy
conclusions :early thoracic
irradiation improves progressionfree survival and overall survival
22
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Pre-Chemo vs Post-Chemo
Volumes
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Kies, et al. J Clin Onc. 4:592-600, 1987. – SWOG
Liengswangwong, et al. J Clin Onc. 12:496-502, 1994. - Mayo
Clinic

conclusions : use of post-chemo tumor volume
did not
– increase the risk of marginal recurrence
– Improve median survival
– Improve median RFS
AT Turrisi, et al. NEJM. 1999. - ECOG
QD RT = 45 Gy in 1.8 Gy fx qd
BID RT = 45 Gy in 1.5 Gy fx bid
QD RT
BID RT
p-value
response rate – overall
87%
87%
NS
CR
49%
56%
NS
PR
38%
31%
NS
19 mo
23 mo
0.04
2-yr OS rate
41%
47%
0.04
5-yr OS rate
16%
26%
0.04
2 yr failure-free survival rate
24%
29%
0.10
local failure rate
52%
36%
0.06
median survival
treatment related toxicity
QD RT
BID RT
p-value
grade 3-4 myelosuppression
85%
87%
NS
grade 3 esophagitis (unable to swallow solids, narcotic
use, G-tube)
11%
27%
0.001
5%
5%
NS
5 pt
(2%)
6 pt
(3%)
NS
grade 4 esophagitis (hospitalization or perforation)
death
24
PCI – 25Gy/10f

R Arriagada1995. - Institut Gustave-Roussy, France
PCI (n=145)
no PCI (n=149)
p-value
2-yr brain met rate
40%
67%
< 0.0001
2-yr survival rate
29%
21%
NS
conclusions = PCI given to those with complete remission after initial therapy
significantly decreases the risk of brain mets without increasing neurotoxicity at 2.5 yr,
and there is a trend toward improved survival
A Gregor, et al. 1997. – UKCCCR/EORTC
conclusions :
(1)for limited stage SCLC in complete remission after initial
therapy, PCI significantly decreases the likelihood of brain relapse
(2)higher doses were more effective (no difference in brain met
rate was seen with 2400 cGy vs no PCI)
25
PCI- meta-analysis
( LD )
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Auperin, R Arriagada, et al. NEJM. 341:476-484,
1999. - Institut Gustave-Roussy, France
median f/u = 5.5 yr
PCI (n=526)
no PCI (n=461)
p-value
3-yr OS rate
21%
15%
0.01
3-yr DFS rate
22%
13.5%
0.001
3-yr brain mets rate
33%
59%
0.001
3-yr other mets rate
42%
46%
NS
3-yr LRR rate
44%
45%
NS
conclusions : addition of PCI in pt with limited stage SCLC in complete remission
26
after chemo results in significantly improved
3-yr OS and DFS and 50% reduction in the incidence of brain mets.
Prophylactic cranial Irradiation in Extensive Small Cell Lung Cancer ( NEJM )
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Inclusion Criteria :
Age 18 -75
PS (0 – 2)
Documented extensive SCLC before starting CTR
Response after 4 – 6 cycle
Interval of no more than 5/52 between the last cycle of CT
and Radiation
No evidence of brain metastases
No Hx of Rad to H/N area
No Hx of CS use
No Previous or other current cancer
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PCI :2 lateral fields
Co , 4 – 18 MV
Daily RX / 5 weeks
Dose was 20Gy / 5–8 fx
24 Gy / 12 fx
25 Gy/ 10 fx
30 Gy/ 10 –12 fx
. Radiation started 4 – 6 weeks after CT
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Point in the study:End Point : Development of symptomatic brain
metastases including :
12345-
HA
N/V
cognitive or affective disturbance
Seizures
Focal neurological symptoms
Role of PCI ??
The role of PCI in patient who do not have complete response to
CTR is unclear
- Usually they don’t have complete response
Results
Patient in the irradiation group had a lower
risk of symptomatic brain metastases
- Cumulative risk of brain metastases within 1
year was :
14.6% in the irradiation group.
40.4% in the control group .
- The 1 year survival rate was 27.1% in
irradiation group and 13.3% in the control
group.
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Cumulative Incidence of Symptomatic Brain
Metastases .
Disease-free Survival
Overall Survival
Conclusion:
PCI reduce the incidence of symptomatic brain
met
and prolongs DFS + OS
Current Standard Regimens
for First-Line Therapy
LD
Cisplatin 60–80 mg/m2 d 1
Etoposide 80–120 mg/m2 d 1-3
Concurrent RT (45–50 Gy)
q 3 wk†
ED
Cisplatin 60–80 mg/m2 d 1
Etoposide 80–120 mg/m2 d 1–3
q 3 wk†
or
or
Carboplatin AUC 6 d 1
Carboplatin AUC 5–6 d 1
Etoposide 80–100 mg/m2 d 1–3
Concurrent RT (45–50 Gy)*
q 3 wk‡
Etoposide 80–100 mg/m2 d 1–3
q 3 wk‡
AUC = area under the plasma concentration-versus-time curve.
*May be 45 Gy bid.
†Turrisi et al. N Engl J Med. 1999;340:265-271.
‡Hainsworth and Greco. Semin Oncol. 1999;26(suppl 2):60-66.
Outcomes of First-Line Therapy
with Current Standard Options
Complete response (%)
LD
45-75
ED
10-30
Median survival (mo)
15-23
6-11
2-year survival (%)
20-47
10-20
5-year survival (%)
10-26
1-2
NSLC
Staging
MX of NSLC
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1A : SURGEY alone
R/O Rad : 1- Inoperable
2- + ve margin
IIA – 2B (T2N0 , T1N1, T2N1 , T3N0)
Surgey + Chemotherapy ( CALBG , NCIC,IALT )
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R/O Rad : 1- Inoperable
2- + ve margine
3- Nodal ECE
DEFINITIONS
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IIIA (T3 N1 or T1-T3, N2)
– N2 = single-digit nodes (station 1-9)
Station
 Station
 Station
 Station
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7
4
2
5
= subcarinal
= low paratracheal
= high paratracheal
/ 6 = AP window (accessible via anterior med.)
IIIB (any T, N3 or T4
– N3 = ipsilateral scalene or supraclavicular nodes
– T4 = invading major organ or satellite nodule same
lobe
IIIA :
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Operable
1- chemo – restage – if no progression –
surgery –chemo +/- rad if : 1- + margine
2- nodal ECE
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2- Concurrent chemorad ( 45 GY) –restage
–if no progression surgery – chemo
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If progression cont chemorad to (61 Gy)
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ASTRO 2003
RTOG 9309
NSCLC IIIA, pN2
Cisplatin + VP16 q3wk x 2, concurrent with RT
Thoracic RT 45 Gy
Surgery
RT to 61 Gy
2 additional cycles chemotherapy to both groups
RTOG 9309 : NSCLC IIIA, CRT vs CRT + S
Surgery
No Surgery
LF + N + DM
15 %
28 %
Median PFS
14 mo
12 mo
Median survival
22 mo
22 mo
Cancer death
71 %
81 %
Treatment death
11 %
2%
RTOG 9309 : NSCLC IIIA, CRT vs CRT + S
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Surgery reduces progression but is
associated with more treatment deaths
More cancer deaths in no surgery
group, despite more chemotherapy
Despite significantly improved PFS ,
surgery did not improve overall
survival
Longer F/U may demonstrate a benefit
Stage IIIA
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Approximately 20 % of all stage IIIA
resectable
Different clinical gradations of N2 disease,
with differing prognoses:
– Easily visible on CXR / CT = “bulky” N2
– Single station enlarged node
– Normal CT, only positive at mediastinoscopy
– Normal CT, -ve mediastinoscopy, only found at
final, post-resection pathology = “incidental” N2
Inoperable IIIA :
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1- Concurrent chemorad (63 Gy )
+adjuvant chemo ( RTOG 9410 )
2- Induction chemo – rad (sequential)
3- Rdaiation alone
Option depends on patient , PS , Wt
loss.
Radiation and
Chemotherapy for St III
NSCLC
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CALBG 1990
Arm1
RT 60Gy/30f
Arm 11 Vinblastine /CPP x 2 cycles
followed by RT 60Gy/30f
Interim analysis favored combined
modality with median S 13.6 mos vs 9.7
mos
Dillman,R NEJM 1990:323,940
Radiation and
Chemotherapy for St III
NSCLC1
RTOG 88-08
Arm 1
Standard RT 60 Gy/30f
Arm 11 Vinblastine/CPP x 2cycles followed by 60
Gy/30f
Arm 111 RT bid fractionation 69.6 Gy/1.2 Gy/fraction
Results Median S
Arm 1---11.4 mo. Arm 11---13.8 mo.
Arm111---12.3 mo.
Sequential therapy became the standard
J. Nat. Cancer Inst.. 1995: 87,3
Concurrent Chemotherapy and
Radiotherapy St III
RTOG 94-10
 SIII,III, KPS> 70, wt loss <5%
 Arm I
VLB/CPP followed by 63 Gy
 Arm II VLB/CPP concurrent with 63 Gy
 Arm III Oral VP-16/CPP concurrent with bid RT 69Gy
 Results
Median S
 Arm I
14.6 mo.
 Arm II
17 mo.
 Arm III
15.6
 Concurrent therapy has become standard
therapy
IIIB
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IF Localized & no pleural effusion
As IIIA
If pleural effusion or Stage IV
PS ( 0-2) Palliative chemotherapy+Rad
PS (3-4) Best supportive care
RESULTS
Local-Regional Control
 Surgical Stage 1-2:
 Surgical Stage T3/N2:
 After sleeve lobectomy:
5 Year Overall Survival
 Stage I
50%
 Stage II
30%
 Stage IIIa
15%
 Stage IIIb
5%
 Stage IV
1%
 All stages
13%
85-90%
80%
60%
Survival Curves Lung Cancer
50%
30%
17%
2%
Pancoast's syndrome and
superior (pulmonary) sulcus
tumors
PANCOAST

Tumors located at the upper part of
the pulmonary sulcus near the thoracic
inlet may correctly be regarded as
superior sulcus tumors, although the
inferior margins of the superior sulcus
are not well defined.
CLINICAL PRESENTATION
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Lesions in the superior sulcus may result in:
shoulder and arm pain (in the distribution of
the C8, T1, and T2 dermatomes)
Horner's syndrome, and weakness and
atrophy of the muscles of the hand, a
constellation of symptoms referred to as
Pancoast's syndrome .
The majority of patients with superior
sulcus tumors present with one or more of
these complaints.
CLINICAL PRESENTATION


shoulder and arm
pain (in the
distribution of the
C8, T1, and T2
dermatomes)
Horner's syndrome,
and weakness and
atrophy of the
muscles of the
hand.
What is make it
unresectable?
Involvement of :
1. Brachial plexus grossly
2. Subclavin artery
3. Vertebral body
4. Esophagus
5. Medistainal L.N
6. Distance Metastasis
Induction chemoradiation and surgical resection for non-small
cell lung carcinomas of the superior sulcus T3 - T4 N1:
SWOG,IG(PhaseII) ROUCH
CONCLUSIONS:
(1) This combined modality
treatment is feasible in a
multi-institutional setting.
(2) the pathologic complete
response rates were high
(3) resectability and overall
survival were improved
compared with historical
experience, especially for
T4 tumors, which usually
have a grim prognosis.
2 y survival
55%
Complete
resection
70%
CR or micro
residual
65 %
tx related
death
3 patients