Management of small cell lung cancer

1. Small cell lung
cancer
Dr Astha Srivastava
SR,Deptt of
Radiotherapy,SRMSIMS

2. Introduction
• Lung cancer has been the most common cancer in the world for
several decades. There are estimated to be 1.8 million new
cases in 2012 (12.9% of the total), 58% of which occurred in the
less developed regions.
• The disease remains as the most common cancer in men
worldwide (1.2 million, 16.7% of the total
• The highest estimated rates are in Northern America (33.8) and
Northern Europe (23.7) with a relatively high rate in Eastern
Asia (19.2) and the lowest rates again in Western and Middle
Africa (1.1 and 0.8 respectively).
• Lung cancer is the most common cause of death from cancer
worldwide, estimated to be responsible for nearly one in five
(1.59 million deaths, 19.4% of the total).

3. Small cell lung cancer
• Mostly caused by cigarette smoke.
• Kills approximately 30,000 people each year in
the U.S.
• Is a neuroendocrine tumor.
• Highly sensitive to chemotherapy and
radiotherapy, but recurrence is common.

4. Paradoxical combination of good response and
high relapse !!!

5. Epidemiology
• Accounts for 10 -20% of all lung cancers in
males.
• 10-30% in women.
• In India accounts for ~ 15% of all lung cancers.
• Commonly seen in middle aged smoker (5th - 6th
decade in India)

6. Etiology
• Cigarette smoking is the single most important
risk factor for development of SCLC.
• Exposure to asbestos, benzene, coal tar, and
radon gas.

7. Genetic Alterations Associated with
Small Cell Lung Cancer
Tumor Suppressor Genes Protooncogenes
RASSF1A Myc
FHIT Bcl-2
Retinoic acid receptor-beta c-Kit
p53 c-Met
RB IGF-1
Telomeres TGF-B
G protein–coupled receptors

8. Gross
Tumors are white-tan, soft, friable, and often
show extensive necrosis.

9. Microscopic pathology
According to the World Health
Organization lung cancer
classification of 1999-a malignant
epithelial tumor consisting
• Scant cytoplasm.
• Ill-defined borders.
• Finely granular "salt and pepper"
chromatin.
• Absent or inconspicuous nucleoli.
• Frequent nuclear molding.
• A high mitotic count.

10. • Grading criteria
Grade Histology Conventional Nomenclature
Low-grade NE Ca <3 mitotic figures x 10 hpf
Absent necrosis
Carcinoid tumor
Intermediate-
grade NE Ca
>3 but <10 mitoses x 10 hpf
Necrosis
Atypical carcinoid
High-grade NE Ca
Small cell type >10 mitoses x 10 hpf
Necrosis
Small cell carcinoma
Large Cell NE Ca > 10 mitoses x10 hpf
Necrosis
Large cell NE Ca

11. Clinical Presentation
• SCLC is a rapidly growing and aggressive tumor.
• Patients develop symptoms over a short period
of time and are usually diagnosed within 3
months from onset of symptoms.

12. • Most common symptoms at presentation are
worsening of cough, shortness of breath and
dyspnoea.
• Others- chest pain, hoarseness, malaise,
anorexia, weight loss, hemoptysis.
• Hemoptysis and postobstructive pneumonia are
relatively uncommon due to the submucosal
growth pattern of the tumor.

13. • Spread to the mediastinal lymph nodes is a
hallmark of SCLC, and syndromes resulting
from mass effect are commonly seen.

14. Paraneoplastic syndrome

15. Staging
Staging Systems
• American Joint Committee on Cancer (AJCC)
Tumor, Node, and Metastasis (TNM).
• Veterans Administration Lung Study Group
(VALG).
• International Association for the Study of Lung
Cancer (IASLC).

16. • Limited-stage disease : SCLC is confined to the
hemithorax of origin, the mediastinum, or the
supraclavicular nodes, which can be
encompassed within a tolerable radiation therapy
port.
• Extensive-stage disease : SCLC has spread beyond
the supraclavicular areas and is too widespread
to be included within the definition of LD.
Patients with distant metastases (M1) are always
considered to have ED.

17. • Patients with pleural effusion, massive
pulmonary tumor, and contralateral
supraclavicular nodes have been both
included within and excluded from LD by
various groups.

20. Survival
• Limited disease :16-24 months
• Extensive disease: 6-12 months
• Without treatment SCLC: 2 to 4 months

21. Investigative Workup
• To establish diagnosis:
– FOB
– FNAC
• To stage the disease:
– CXR
– USG
– CT Chest, abdomen(liver, adrenals)
– MRI Brain/CT Brain
– PET/Bone scan- For patients with limited-stage disease, bone scan and
bone marrow aspiration or biopsy are indicated if the lactic dehydrogenase
is elevated, and thoracentesis is indicated if pleural effusion is present.
• Blood investigations
– Hemogram
– Biochemistry : RFT, LFT
– S.LDH

22. Treatment
Limited-stage disease -CT+ Thoracic RT(preferred)
-Combination CT
-Lobectomy+/- mediastinal
node dissection or sampling followed by CT or CRT
-Prophylactic cranial irradiation
Extensive-stage disease -Combination CT(preferred)
-Radiotherapy
- Prophylactic cranial irradiation
Recurrent disease - Chemotherapy
- Palliation therapy

23. Chemotherapy
• Chemotherapy improves the survival of patients
with limited-stage disease or extensive-stage
disease , but it is curative in only a minority of
patients.
• With incorporation of current chemotherapy
regimens into the treatment program, however,
survival is prolonged, with at least a fourfold to
fivefold improvement in median survival
compared with patients who are given no
therapy.

24. • The combination of platinum and etoposide is the most
widely used standard chemotherapeutic regimen.
• Adjuvant chemotherapy is recommended for those who
have undergone surgical resection.
• No consistent survival benefit has resulted from-
1.platinum versus nonplatinum combinations 2.increased
dose intensity or dose density
3. altered mode of administration (e.g., alternating or
sequential administration) of various chemotherapeutic
agents
4.maintenance chemotherapy.

25. • Relapsed SCLC: Topotecan

26. cisplatin/irinotecan versus
cisplatin/etoposide in SCLC ED
Japanese experience
Noda et al. NEJM 2002

28. Radiation therapy
Curative:
– With Chemotherapy in localized SCLC
Palliative:
– For palliation of symptoms due to primary growth
– In SVCO
– For palliation of bone mets
– For palliation of brain mets
Preventive:
– For prophylactic cranial irradiation

29. • SCLC is highly radiosensitive and thoracic
radiation therapy improves survival of patients
with LD and ED tumors.
• For LD :45 Gy ,1.5Gy /#,in 3 weeks twice daily
45 Gy in 5 weeks twice daily
60-70 Gy once daily regimen

30. • GTV + 1.5 cm
• Ipsilateral hilar region+mediastinum
( from thoracic inlet and includes subcarinal
region)
• If Subcarinal involvement (+), inferior border is
5 cm below carina
• No contralateral hilar region and
supraclavicular lymphatics are included within
RT portal if not involved.

31. Chemotherapy and radiation therapy
• Combined-modality treatment with etoposide and
cisplatin with thoracic radiation therapy is the most
widely used treatment for patients with limited-stage
disease SCLC.
• Evidence (combined modality treatment):
Survival
– Mature results of prospective randomized trials suggest
that combined-modality therapy produces a modest but
significant improvement in survival of 5% at 3 years
compared with chemotherapy alone.
– Clinical trials have consistently achieved median survivals
of 18 to 24 months and 40% to 50% 2-year survival rates
with less than a 3% treatment-related mortality.

32. A meta-analysis of thoracic RT in LD-SCLC
12 phase III studies
Pignon et al NEJM 1992

33. Concurrent vs Sequential CCT
• accepted that concurrent
chemoradiation is better than
sequential chemoradiation.
• Takada et al (2002): JCOG
– Used CE
– RT dose 45 Gy in 30# @ 1.5 Gy per
fraction bid over 3 weeks
– Median survival improved from 19
months to 27 months

34. But…
• Controversy still exists about relative superiority of CCRT
• Most of patients present with ED
• Even patients with LD have:
– Poor performance scores
– Bulky disease
– Poor pulmonary functions
– Several co-morbidities
– Incompliance with an aggressive regimen
• CCRT has a high in treatment mortality ( 7 -10%) in various
series

35. Length of treatment:
• The optimal duration of chemotherapy for
patients with LD SCLC is not clearly defined
• No improvement exists in survival after the
duration of drug administration exceeds 3 to 6
months.
• Maintenance chemotherapy does not prolong
survival for patients with LD SCLC

36. • Dose and timing.
The optimal dose and timing of TRT remains
controversial.
– Multiple clinical trials and meta-analyses with the
weight of evidence suggesting a small benefit to
early TRT .
– In an analysis of four trials, the completion of
therapy in less than 30 days was associated with
an improved 5-year survival rate .

37. – Both once-daily and twice-daily chest radiation schedules
have been used in regimens with etoposide and cisplatin.
– One randomized study showed a modest survival
advantage in favor of twice-daily radiation therapy given
for 3 weeks compared with once-daily radiation therapy to
45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).
Esophagitis was increased with twice-daily treatment.
– Twice-daily radiation therapy has not been broadly
adopted. Once-daily fractions to higher doses of greater
than 60 Gy are feasible and commonly used; their clinical
benefits are yet to be defined in phase III trials.

38. Prophylactic cranial irradiation
• Patients who have achieved a complete remission
can be considered for administration of PCI.
• Patients whose cancer can be controlled outside
the brain have a 60% actuarial risk of developing
central nervous system (CNS) metastases within 2
to 3 years after starting treatment
• The risk of developing CNS metastases can be
reduced by more than 50% by the administration
of PCI.

39. • Not performed in patients with poor
performance status or impaired
neurocognitive functioning.
• Dose: 25 Gy /10#

40. Role of PCI:
• A meta-analysis of seven randomized trials evaluating the value of
PCI in patients in complete remission reported improvement in
brain recurrence, disease-free survival, and OS with the addition of
PCI. The 3-year OS was improved from 15% to 20% with PCI.
• A randomized study (RTOG-0212) of 720 patients with LD SCLC in
complete remission after chemoradiation therapy demonstrated
that standard-dose PCI (25 Gy in 10 fractions) was as effective as
and less toxic than higher doses of brain radiation.
• Randomized trials such as EORTC-22003-08004 (NCT00005062)
showed that doses higher than 25 Gy in 10 daily fractions do not
improve long-term survival.

41. SCLC - Meta-analysis of PCI
From 7 randomised trials of PCI vs no-PCI
Patients 987 (140 patients had ED-SCLC)
Chemo- & RT schemes various
Overall survival benefit +5% (95% CI: 1 -10%)
3 year survival 20 vs 15%
Incidence of brain mets 33 vs 59%
Auperin et al. NEJM 1999

42. Very limited stage disease
• Stage I(T1-2,N0) , mediastinal staging to be
ruled out for involved mediastinal nodes
before resection
• Lobectomy is preferred
• Adjuvant RT(without nodal mets) or
chemoRT(with nodal mets) is recommended.

43. SCLC metastasis.
• Liver (27%)
• Bone (41%)
• Adrenals (31%)
• Brain (14%)
• Lymph nodes mediastinal (80%)

44. Prognostic factors
• Poor performance status
• Extensive stage disease
• Weight loss
• Raised LDH

45. Follow up
1-2 years 3-5 years >5 years
3-4 months Every 6 months annually

47. Ongoing trials
• CALGB 30610/RTOG 0538: Three Different Radiation
Therapy Regimens in Treating Patients with Limited-Stage
Small Cell Lung Cancer Receiving Cisplatin or Carboplatin
and Etoposide.
• CA209-331 Efficacy Study of Nivolumab or Chemotherapy
in Subjects With Relapsed Small-cell Lung Cancer.
• Olaparib and Temozolomide in Treating Patients with
Recurrent Small Cell Lung Cancer

48. THANK YOU