Small cell ca lung

INTRODUCTION
 15-20% of lung cancer patients
 In USA (2011) : 28,000 patients diagnosed (13% all lung
cancer diagnoses)
 Median age of diagnosis 70 years
 Rapid tumor growth and early metastatic spread
 If untreated, rapid progression and median survival 2-4
months
 60% present with Extensive stage with 2 year survival of
4%
Perez and brady’s principles and practice of radiation oncology (sixth edition)

Smoking and Small Cell Ca Lung
 Only 2% to 3% of patients with this malignancy are never
smokers
DeVita, Hellman, and Rosenberg’s Cancer
Principles & Practice of Oncology 10th edition

PATHOLOGY
 Dense sheets of
small cells
 Scant cytoplasm
 Finely granular
nuclear chromatin
 Inconspicuous or
absent nucleoli
 Frequent mitoses
 Necrosis is
common

IHC
 CD56
 Chromogranin
 Synaptophysin
 Upto 10% of SCLCs may be negative for all
neuroendocrine markers
 A high proliferation rate of 80% to 100% should be seen
with Ki-67
 Thyroid transcription factor-1 (TTF-1) is positive in 70% to
80% of small cell carcinomas

PARANEOPLASTIC SYNDROMES
 Neurological
 ACTH ( Cushing’s syndrome)
 ADH ( SIADH )
 Ectopic production of atrial natriuretic factor contributes
to the disorder in sodium homeostasis

Neurologic
 Sensory, sensorimotor, and autoimmune neuropathies
and encephalomyelitis
 Most frequent : Subacute peripheral sensory neuropathy
 Lambert-eaton syndrome : autoantibody impairment of
voltage-gated calcium channels; characterized by
proximal muscle weakness that improves with continued
use, hyporeflexia and dysautonomia.
 Rare : cerebellar degeneration or retinopathy

Staging System - VALSG
 Veterans administration lung study group
 Limited-stage (LS)
 Disease confined to one hemithorax, although local
extension may be present
 No extrathoracic metastases except for ipsilateral
supraclavicular lymph nodes if they can be included in the
same radiation port as the primary tumor
 Primary tumor and regional nodes that can be adequately
encompassed in a radiation portal.
DeVita, Hellman, and Rosenberg’s Cancer Principles & Practice of
Oncology 10th edition

Extensive-stage
 Defined as disease that cannot be classified as limited,
including malignant pleural or pericardial effusions,
contralateral hilar or supraclavicular lymph nodes, and
hematogenous metastases

Surgical Management : T1-2 N0
 < 5% of cases
 Definitive Surgical Resection
 Invasive staging of mediastinum to be done prior to
surgery
 Population Based Study : 50% OS with surgery and
without RT
 Mode of Failure : Distant Dissemination
DeVita, Hellman, and Rosenberg’s Cancer Principles & Practice of Oncology 10th edition

JCOG TRIAL - Concurrent vs Sequential
Chemotherapy and Thoracic Irradiation
 N = 231
 Dose : 45 Gy over 3 weeks (1.5 Gy twice daily)
 Arm 1 : 4 cycles of Cisplatin and Etoposide every 4 weeks
concurrent with Radiotherapy – Beginning D2
 Arm 2 : 4 cycles of Cisplatin and Etoposide every 3 weeks
sequentially before Radiotherapy

Conclusion
 This study strongly suggests that cisplatin plus etoposide
and concurrent radiotherapy is more effective for the
treatment of LS-SCLC than cisplatin plus etoposide and
sequential radiotherapy.
 Hematologic toxicity was more severe in the concurrent
arm

Early versus Late Radiotherapy
 Early radiation therapy : Beginning before 9 weeks after
the initiation of chemotherapy and before the third cycle
of chemotherapy.
 Late radiation therapy : Began 9 weeks or more after the
initiation of chemotherapy or after the beginning of the
third cycle

Systematic Review Evaluating the
Timing of Thoracic Radiation
Therapy in Combined Modality
Therapy for Limited-Stage Small-
Cell Lung Cancer
 Fried et al

Conclusion
 The use of early thoracic radiotherapy, with cycle 1 or 2 of
chemotherapy, was associated with improved 2-year OS
compared to delayed or sequential chemotherapy and
radiation.
 The benefit was more pronounced when the radiotherapy
was given with platinum- based chemotherapy.

Dose and Fractionation
 Area of active investigation
 Radiosensitive : Hence hyperfractionated can be done
 High proliferative rate : Hence accelerated treatment can
be done
Perez and brady’s principles and practice of radiation oncology (sixth edition)

Twice-daily compared with once-
daily thoracic radiotherapy in
limited small-cell lung cancer
treated concurrently with cisplatin
and etoposide
 Turrisi et al

 Randomized, Intergroup trial of concurrent accelerated
hyperfractionated radiotherapy versus standard daily
radiotherapy in patients with limited-stage SCLC
 N = 417
 Chemotherapy : EP X 4 cycles
 Dose of RT : 45Gy total
 Arm 1 : 1.8Gy @ Once daily over 5 weeks
 Arm 2 : 1.5 Gy @ Twice daily over 3 weeks

Results
 OS was significantly higher in the twice-daily arm, 26%
versus 16% at 5 years, and local recurrence was
significantly lower, 36% versus 52%
 Grade 3 esophagitis
 Twice-daily group : 27 percent
 Once-daily group : 11 percent (P<0.001)
 No difference in late toxicity

RADIOTHERAPY VOLUME
 SWOG Trial : Pre induction volume v/s Post induction volume :
No difference in local recurrence rate
 Intergroup trial : Included gross disease, the bilateral
mediastinum, and the ipsilateral hilum in the treatment field.
 RTOG- 9712261 : Included uninvolved supraclavicular area in
the setting of apical tumors
 Consultants from the International Atomic Energy Agency
reviewed available literature in 2008 and found little evidence
to guide the use of elective nodal irradiation
DeVita, Hellman, and Rosenberg’s Cancer Principles & Practice of Oncology 10th
edition

 Patients with extensive-stage disease are usually treated
with systemic chemotherapy alone.
 For select good performance status patients with
extensive-stage disease who have complete resolution of
their extra thoracic tumour burden, consolidative thoracic
radiotherapy may be of benefit

1970
• Alkylating agents, anthracyclines, vinca alkaloids, antifolates all showed
single-agent efficacy
1980
• Randomized trials of combinations demonstrated superior activity to single
agents
• Livingston et al developed the cyclophosphamide, doxorubicin, vincristine
(CAV) combination : the standard chemotherapy regimen
1990
• Etoposide identified as perhaps the most active agent

Cisplatin vs Carboplatin
 Meta-analysis : 4 randomized trials (N : 663)
 Median overall survival (OS), median progression-free survival
(PFS), and response rates were similar in the cisplatin and
carboplatin arms.
 Although hematologic toxicities were higher in those patients
that receive carboplatin, nonhematologic toxicities were
increased in those that receive cisplatin.
 Based on these data, etoposide and carboplatin can be
considered an appropriate first-line regimen, particularly in
patients who cannot tolerate cisplatin.

Irinotecan
Japan Clinical Oncology
Group
The Southwest Oncology
Group
 Cisplatin and irinotecan to EP
 Median survival : 12.8 months
versus 9.4 months
 2-year survival : 19.5% versus
5.2%
 Significant diarrhea occurred only
in the irinotecan group, and
myelosuppression was the most
common toxicity in both groups
and more frequent with EP.
 Compared these two regimens
with the same dose and
schedule used in the Japanese
trial and also showed, in a well-
powered study, that outcomes
are equivalent with the two
regimens

Topotecan
 Eckardt et al.
 N = 784 patients
 Arm 1 : oral Topotecan (1.7 mg/m2 per day for 5 days)
plus Cisplatin
 Arm 2 : Standard Etoposide and Cisplatin
 The response rates, median survival, and 1-year survival
were identical.
 Severe neutropenia occurred more often with EP, but oral
Topotecan and Cisplatin caused more anemia and
thrombocytopenia
DeVita, Hellman, and Rosenberg’s Cancer Principles & Practice of Oncology 10th
edition

Alternating Cycles of Combination
Chemotherapy Regimens
 Somatic mutation model : Goldie et al
 Predicted that the best probability of cure was achieved by the earliest
possible introduction and the most rapid alternation of all active agents.
 If two equally effective non–cross-resistant regimens were available, the
model predicted that alternating between regimens every other cycle
would be more effective than alternating after every three cycles or giving
one regimen continuously or five cycles before switching to the second
regimen.

Addition of a Third Chemotherapeutic
Agent to Etoposide Plus Cisplatin
 All efforts to add a third drug to the standard EP regimen have
resulted in more toxicity with little or no improvement in
survival
 Etoposide, Ifosfamide, Cisplatin (VIP)
 Ifosfamide, Carboplatin, Etoposide (ICE)
 ICE plus a midcycle dose of vincristine to other standard
therapy demonstrated an improvement in the median and 1-
year survival rates. However, an increased rate of septicemia
was noted (ICE-V 15% versus 7% in the control arm).

Trial Design Results Remarks
CALGB 258 patients
randomized to 4
chemo
armsCRsecond
randomization
Median survival
Observation arm : 7
months
Maintenance arm : 17
months
initial regimens used
in this study
might be considered
inferior to currently
used treatments
ECOG CAV + 3 drug
CAV alone CR
second randomization
CAV + Maintenance :
Longer PFS/OS
compared to
observation arm (p
0.09)
for the patients who
received the six-drug
regimen, those who
were given no
maintenance survived
longer than the
patients who
received maintenance
treatment
Medical Research
Council
6 cycles chemo-
respondersupto 6
more cycles or
observation
No difference in
survival

Conclusion
 Four to six cycles of chemotherapy appear to be optimal
in the management of limited and extensive SCLC.
 After the completion of this initial treatment, patients
should be monitored closely and then offered further
chemotherapy at the time of progression.
 Both the NCCN and the ESMO guidelines support this
approach

 Several investigators evaluated whether increasing the
dose of drugs beyond the usual dose improves survival.
 Three randomized trials comparing standard versus high-
dose CAV or EP found no difference in response rates or
median survival
 A number of studies have evaluated whether shortening
the interval between chemotherapy cycles improves
survival : no survival benefit was identified
 Conclusion : Survival has not been shown to be better
than conventional treatment.

SENSITIVE REFRACTORY
 An appropriate response to initial
therapy that is maintained for 3
months or more
 These patients have a higher
likelihood of response to any
additional chemotherapy;
although, at best, it is
approximately half that
expected in the first-line
setting.
 Survival from the start of a
second regimen averages
around 6 months.
 No response to initial therapy
or progressed within 3 months
after completing treatment.
 Their chance of response to
additional therapy is less than
10%
 Their median survival from the
start of a second regimen is 4
months.

Topotecan
 The only approved agent in relapsed disease
 Ardizzoni et al
 Administered at a dose of 1.5 mg/m2 daily for 5 days,
yielded a response rate of 38% in sensitive patients and
6% in refractory patients.
 Median survival from the start of second-line therapy was
7 and 5 months, respectively.

Oral Topotecan
 In a randomized phase II study, oral topotecan at a dose
of 2.3 mg/m2 daily for 5 days was comparable to
intravenous topotecan 1.5 mg/m2 daily for 5 days with
regard to response rate (23% versus 15%), median
survival (32 weeks versus 25 weeks), and symptom
control

Other drugs
 Amrubicin
 Temozolomide
 Paclitaxel
 Docetaxel
 Gemcitabine

 Imatinib : TKI - No response
 Cixutumumab : IGFR antibody – No improvement in PFS
 Thalidomide : No improvement in survival
 Bevacizumab : VEGF antibody – improved PFS but not in
OS
 Bortezomib : Proteasome inhibitor – 2% overall response
rate

 Brain metastases are detected in at least 18% of SCLC
patients at diagnosis and eventually are diagnosed in
another 20% to 25%, with an increasing likelihood seen
with lengthening survival.
 An actuarial analysis reveals a probability of brain
metastases ranging from 50% to 80% in patients who
survive 2 years.
 Because these metastases are sometimes the sole site of
clinical relapse and are frequently clinically disabling, PCI
has been recommended

Results and Conclusions
 Prophylactic cranial irradiation improves both overall
survival and disease-free survival among patients with
small-cell lung cancer in complete remission
 Larger doses of radiation led to greater decreases in the
risk of brain metastasis but the effect on survival did not
differ significantly according to the dose
 There is also a trend toward a decrease in the risk of brain
metastasis with earlier administration of cranial
irradiation after the initiation of induction chemotherapy.

Intergroup trial - Standard-dose versus
higher dose PCI after complete response for
limited-stage disease
 N =720
 25 Gy in 10 fractions
 36 Gy delivered in 18 daily fractions of 2 Gy or 24 twice-daily
fractions of 1.5 Gy
 There was no significant difference in incidences of brain metastases
between the standard-dose group and the high-dose group
 This study established 2,500 cGy in 10 fractions as the standard dose
of PCI for limited-stage patients

 Randomly assigned to
undergo prophylactic
cranial irradiation
(irradiation group) or
receive no further
therapy (control group)
 Conclusion : Prophylactic
cranial irradiation reduces
the incidence of
symptomatic brain
metastases and prolongs
disease-free and overall
survival.

Small cell ca lung

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