2. INTRODUCTION
• Tobacco consumption is the primary cause of small cell lung cancer.
• Voluntary or involuntary cigarette exposure accounts for 80% to 90% of all cases
of Lung cancer.
• Indoor Radon exposure is now the 2nd cause of Lung cancer in USA
• Other known risk factors are-
• Occupationl and environmental carcinogens-
• Asbestos
• Arsenic and
• Polycyclic Hydrocarbons
3. EPIDEMIOLOGY
In the world small cell lung cancer accounts for 13% of all lung cancer
cases.
Lung cancer is rare below age 40, with rates increasing until age 80, after
which the rate tapers off.
The natural history of untreated SCLC included rapid tumor progression
with a median survival of only 2 to 4 months.
Approximately two thirds of patients with SCLC have extensive-stage or
stage IV disease at presentation
4. HISTOLOGY
Histologically, SCLC is one of the small, round, blue cell tumors (along
with neuroblastoma, rhabdomyosarcoma, Merkel cell carcinoma, etc.)
with scant cytoplasm and indistinct nucleoli.
6. CLINICAL FEATURES
• Because of the high frequency of extensive mediastinal and hilar nodal
involvement in SCLC cases, patients frequently present with symptoms
such as
Dyspnea,
Dysphagia,
Hoarseness, And
Superior vena cava (SVC) syndrome.
• Many patients with SCLC present with other thoracic symptoms including
Cough,
Hemoptysis,
Chest Pain, And
Weight loss.
7. SUPERIOR VENA CAVA SYNDROME
• Results from obstruction of blood flow to the heart from the head and
neck regions and upper extremities.
• It occurs as a consequence of compression of the superior vena cava,
either from direct invasion by the primary tumor into the mediastinum
or from lymphatic spread with enlarged right paratracheal lymph
nodes.
• It is commonly caused by SCLC but can result from any centrally located
tumor or mediastinal spread.
8. Features-
1. Feeling of fullness in the head
2. Dyspnea
3. Cough
4. Dilated neck veins
5. Prominent venous pattern on the face and the chest
6. Upper extremitt and facial edema
7. Pappiledema
8. Facial cyanosis
9. Plethora
10. Conjunctival edema(possibly)
10. SIADH – Small cell –
It results into Hyponatremia
Symptoms include-Headache,Muscle cramps,Anorexia & Decreased urine
output
Resolves within 1–4weeks of initiating chemotherapy.
Demeclocycline is the agent of choice
Cushing Syndrome-ACTH-producing tumors – Small cell-
Symptoms-Muscle weakness,weight loss,hypertension,hirsutism & osteoporosis.
Hypokalemic alkalosis and hyperglycemia are present.
It has worse prognosis
11. Lambert-Eaton Myasthenic Syndrome(LEMS)
It is characterized by muscle weakness of the limbs.
Proximal muscles are affected associated with difficulty in climbing chairs
and rising from a sitting position.
Chemotherapy is the initial treatment of choice.
Neurologic–
Encephalomyelitis
cerebellar degeneration
retinopathy.
13. DIAGNOSTIC WORK UP
• Complete history
• Complete physical examination
Chest-may show signs of-
I. Partial or complete obstruction of airways
II. Pneumonia
III. Pleural Effusion
Neck Examination-Signs of Supraclavicular lymphadenopathy
Abdominal examination-signs of hepatomegaly
Neurological examination-signs of Brain metastais
14. Haemogram
• CBC-anemia due to metastatic disease
• LFT-May indicate Liver mets
• Increased ALP-May indicate Liver or Bone mets
• Increased Calcium ion-May indicate Bone mets or Paraneoplastic
syndrome
15. RADIOLOGIC EXAMINATIONS
• Chest Xray-initial imaging modality.
• Current Xray should be compared with previous ones to determine if a lesion is-
• New
• Enlarging or
• Stable
• CT Scan-
• CECT Chest + Upper Abdomen should be done so that Liver and Adrenals can be
visualized
• In a patient with known lung cancer a lymph node is considered suspicious if it
measures >1cm in diameter on its short axis.
16. • It can establish T stage by-
I. Determining tumor size
II. Presence of separate tumor nodules
III. Presence of atelectasis
IV. Post obstructive pneumonia
V. Invasion of adjacent structures
VI. Proximal extent of the tumor
• PET or PET-CT SCAN
• It has become standard in the staging work up of lung cancer patients.
• The biggest advantage is the identification of suspicious lymph nodes or distant
metastasis.
17. • Kaeff et al prospectively evaluated the utility of PET-
• They found that PET correctly upstaged 26% patients
• and downstaged 10-16 patients.
• Additionally PET can detect malignant disease in lymph nodes of normal size.
• PET-CT is superior to CT or PET alone and can detect malignancies in tumors as
small as 0.5cm.
• Novel tracers-
• FDG
• FMISO(18F-fluoromisonidazole)-For tumor Hypoxia
• FLT(18F-fluorothymidine)-For tumor proliferation
• 11C-methionine and 11C-tyrosine-For amino acid metabolism.
18. • Sputum Cytology-Sensitivity is 65%.
• Percutaneous Fine Needle Aspiration(FNA)-
• CT guided FNA done in lesions which cannot be reached by Bronchoscopy.
Overall diagnostic yield is 80%.
• Bronchoscopy-
• FOB is done and cytologic brushings,biopsies can be taken.
19. Biopsy - confirm the cancer and determine
the type
Bronchoscopy CT guided biopsy
20. • Endoscopic FNA-
• Endobronchial USG guided transbronchial needle aspiration(EBUS-TBNA) can be
done for ultrasound suspicious lymph nodes-
Paratracheal-Level 2 & 4
Subcarinal-Level 7
Hilar lymph node stations-level 10
• Thoracocentesis-
• If on multiple taps of pleural
fluid is consistently bloody
or exudative ,it should be
considered malignant.
21. • Thoracoscopy
• Video assisted thoracoscopy(VAT) is used for-
I. Diagnosis
II. Staging
III. Resection of lung cancer
• Peripheral nodules can be easily seen and excised.
• It can also be used to reach mediastinal nodes not accessible by standard
mediastinoscopy,EBUS-TBNA or EUS-FNA techniques.
22. PROGNOSTIC FACTORS
The most clinically important prognostic factor in SCLC is
1. stage (limited vs. extensive), with a median survival of
approximately 23 months for patients with limited disease versus 8
to 9 months for those with extensive disease.
2. Clinical factors consistently reported to correlate with improved
survival include
I. good performance status,
II. female gender, and
III. normal lactate dehydrogenase levels at baseline.
23. AJCC STAGING
8th Edition
• Tx
• Primary tumor cannot be
assessed, or tumor proven by
the presence o f malignant cells
in sputum or bronchial washings
but not visualized by imaging or
bronchoscopy
7th Edition
• Tx
• Primary tumor cannot be
assessed, or tumor proven by
the presence of malignant cells
in sputum or bronchial washings
but not visualized by imaging or
bronchoscopy
24. T0
• No evidence of primary tumor • No evidence of primary tumor
25. Tis
• Carcinoma in situ
• Squamous cell carcinoma in situ
(SCIS)
• Adenocarcinoma in situ (AIS):
adenocarcinoma with pure
lepidic pattern, ≤ 3 cm in
greatest dimension
• Carcinoma in situ
26. T1
• Tumor ≤ 3 cm in greatest
dimension, surrounded by lung
or visceral pleura, without
bronchoscopic evidence o f
invasion more proximal than the
lobar bronchus (i.e., not in the
main bronchus)
• Tumor ≤ 3 cm in greatest
dimension, surrounded by lung
or visceral pleura, without
bronchoscopic evidence of
invasion more proximal than the
lobar bronchus (i.e., not in the
main bronchus)
27. • T1mi- Minimally invasive
adenocarcinoma: adenocarcinoma
(≤ 3 cm in greatest dimension) with a
predominantly lepidic pattern and ≤ 5
mm invasion in greatest dimension.
• T1a- Tumor ≤ 1 cm in greatest
dimension. A superficial, spreading
tumor o f any size whose invasive
component is limited to the bronchial
wall and may extend proximal to the
main bronchus also is classified as T1a ,
but these tumors are uncommon.
• T1b- Tumor >1 cm but ≤ 2 cm in greatest
dimension
• T1c- Tumor >2 cm but ≤ 3 cm in greatest
dimension
• T1a Tumor 2 cm or less in greatest
dimension
• T1b Tumor more than 2 cm but 3 cm or
less in greatest dimension
28. T2
• Tumor >3 cm but ≤ 5 cm or having any of
the following features:
• Involves the main bronchus regardless of
distance to the carina, but without
involvement of the carina
• Invades visceral pleura (PL1 or PL2)
• Associated with atelectasis or obstructive
pneumonitis that extends to the hilar
region, involving part or all of the lung
• T2 tumors with these features are
classified as T2a if ≤ 4 cm or if the size
cannot be determined and T2b if >4 cm
but ≤ 5 cm.
• Tumor more than 3 cm but 7 cm or less or
tumor with any of the following features
(T2 tumors with these features are
classified T2a if 5 cm or less); Involves
• main bronchus, 2 cm or more distal to the
carina;
• Invades visceral pleura (PL1 or PL2);
• Associated with atelectasis or obstructive
pneumonitis that extends to the hilar
region but does not involve the entire
lung
29. • T2a Tumor >3 cm but ≤ 4 cm in
greatest dimension
• T2b Tumor >4 cm but ≤ 5 cm in
greatest dimension
• T2a Tumor more than 3 cm but 5
cm or less in greatest dimension
• T2b Tumor more than 5 cm but 7
cm or less in greatest dimension
30. T3
• Tumor >5 cm but ≤ 7 cm in greatest
dimension or directly invading any of the
following:
• Parietal Pleura (PL3),
• Chest Wall (Including Superior Sulcus
Tumors),
• Phrenic Nerve,
• Parietal pericardium; or
• Separate tumor nodule(s) in the same lobe as
the primary
• Tumor more than 7 cm or one that directly
invades any of the following:
• Parietal Pleural (PL3)
• Chest Wall (Including Superior Sulcus
Tumors),
• Diaphragm,
• Phrenic Nerve,
• Mediastinal Pleura,
• Parietal Pericardium; or
• Tumor in the main bronchus (less than 2 cm
distal to the carina* but without involvement
of the carina; or associated atelectasis or
obstructive pneumonitis of the entire lung
• Or separate tumor nodule(s) in the same lobe
31.
32. T4
• Tumor >7 cm or tumor of any size invading
one or more of the following:
• Diaphragm,
• Mediastinum,
• Heart,
• Great Vessels,
• Trachea,
• Recurrent Laryngeal Nerve,
• Esophagus,
• Vertebral Body, Or
• Carina;
• Separate tumor nodule(s) in an ipsilateral
lobe different from that of the primary
• Tumor of any size that invades any of the
following:
• Mediastinum,
• Heart,
• Great Vessels,
• Trachea,
• Recurrent Laryngeal Nerve,
• Esophagus,
• Vertebral Body,
• Carina,
• Separate tumor nodule(s) in a different
ipsilateral lobe
33.
34.
35. M Stage
• M1a- Separate tumor nodule(s) in a
contralateral lobe; tumor with pleural
or pericardial nodules or malignant
pleural or pericardial effusion.
• Most pleural (pericardial) effusions
with lung cancer are a result of the
tumor. In a few patients, however,
multiple microscopic examinations of
pleural (pericardial) fluid are negative
for tumor, and the fluid is non bloody
and not an exudate. If these
elements and clinical judgment
dictate that the effusion is not
related to the tumor, the effusion
should be excluded as a staging
descriptor.
• M1a Separate tumor nodule(s) in a
contralateral lobe tumor with pleural
nodules or malignant pleural (or
pericardial) effusion*
36. • M1b Single extrathoracic
metastasis in a single organ
(including involvement of a
single nonregional node)
• M1c Multiple extrathoracic
metastases in a single organ or
in multiple organs
• M1b Distant metastasis
39. Combining Radiation and Chemotherapy for
Limited-Stage Disease
• A randomized trial by the JCOG evaluated concurrent versus
sequential chemotherapy and thoracic radiation in patients with
limited-stage SCLC.
• All patients received 45 Gy in 1.5-Gy fractions twice daily and were
randomized to receive four cycles of cisplatin (80 mg/m2 on day 1)
and etoposide (100 mg/m2 day 1-3) every 4 weeks concurrent with
radiotherapy (beginning day 2) or every 3 weeks sequentially before
radiotherapy.
• Patients treated concurrently had longer median survival compared
to patients treated sequentially: 27 months versus 20 months.
40. • A second randomized trial by the National Cancer Institute of Canada
compared early with late concurrent chemoradiotherapy.
• In this trial, 308 patients received cyclophosphamide, doxorubicin,
and vincristine alternating with EP and were randomized to 40 Gy in
15 daily fractions given with either the first cycle of EP (week 3) or the
last (week 15).
• The median survival improved to 21 months with early radiotherapy
versus 16 months with late treatment (p = .008).
41. • Fried et al did a meta-analysis that included >1,500 patients from
seven randomized trials evaluating the timing of radiotherapy when
given concurrently with multiagent chemotherapy.
• 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.
42. • The EP (Cis+Etopo) combination is the most commonly used first-line
chemotherapy regimen in patients with SCLC, either alone (in patients
with extensive disease) or in combination with thoracic radiation (in
patients with limited-stage disease).
• In patients with extensive disease, alternative combinations including
cisplatin and irinotecan (IP), the addition of an anthracycline or
taxane to EP, and higher-dose therapy have been investigated;
however, to date, they have not proven superior to EP.
43. Dose and Fractionation
• SCLC is highly radiosensitive, suggesting that hyperfractionation could
be employed to reduce late normal tissue toxicity.
• It also has a high proliferative rate, arguing for accelerated treatment
to counteract repopulation.
44. • 417 patients were enrolled in a randomized, intergroup trial of concurrent
accelerated hyperfractionated radiotherapy versus standard daily
radiotherapy in patients with limited-stage SCLC.
• All patients received four cycles of cisplatin (60 mg/m2 on day 1) and
etoposide (120 mg/m2 on days 1, 2, and 3), and radiotherapy began with
cycle 1.
• In the once-daily arm, patients received 45 Gy in 1.8-Gy fractions over 5
weeks.
• In the twice-daily arm, patients received 45 Gy in 1.5-Gy fractions over 3
weeks.
• Patients who achieved a complete response were offered PCI.
45. • OS was significantly higher in the twice-daily arm, 26% versus 16% at
5 years, and local recurrence was significantly lower, 36% versus 52%.
• There was a significant increase in grade 3 acute esophagitis, 26%
versus 11%, in the twice-daily arm, with no difference in late toxicity.
• The 5-year survival rate observed in this study is among the best
reported for limited-stage disease; consequently, this treatment
approach is considered by many the current standard of care for the
management of limited-stage disease.
46. The optimal dose and fractionation approach for SCLC remains to be defined.
An ongoing intergroup effort (CALGB 30610, RTOG 0538, NCT00632853)
seeks to determine the optimal radiation schedule.
Patients are randomized to one of three arms:
(a) 45 Gy in 30 fractions over 3 weeks
(b) 61.2 Gy in 5 weeks per RTOG 0239 or
(c) 70 Gy in 35 fractions over 7 weeks per CALGB 39808.
47. All patients received concurrent EP, and radiotherapy begins with cycle
1 or cycle 2.
The results are awaited
48. • The Concurrent Once-daily Versus Twice-daily Radiotherapy
(CONVERT) trial is a 2-arm randomized phase III study: patients
receive either 45 Gy in 30 fractions twice daily or 66 Gy in 33 fractions
once daily. All patients receive EP; radiotherapy begins with cycle 2.
49. Result
• Survival outcomes did not differ between twice-daily and once-daily
concurrent chemoradiotherapy in patients with limited-stage small-
cell lung cancer, and toxicity was similar and lower than expected
with both regimens.
• Since the trial was designed to show superiority of once-daily
radiotherapy and was not powered to show equivalence, the
implication is that twice-daily radiotherapy should continue to be
considered the standard of care in this setting.
50. Thoracic Radiotherapy for Extensive-Stage
Disease
• Systemic therapy is the essential element in the treatment of patients with
extensive-stage SCLC with good performance status.
• In a study by Jeremic et al, 209 patients with extensive disease were
enrolled and treated with three cycles of EP (Cis+Etopo).
• Total of 109 patients with response were randomized to: (1) ACC
hypofraction thoracic RT (54 Gy/1.5 Gy twice daily) plus CE (Carbo+Etopo)
and PE × 2, or (2) PE × 4 alone without radiation.
• Overall median survival and 5-year OS were 9 months and 3.4%,
respectively
• Median survival = 17 months (group 1) versus 11 months (group 2); 5-year
OS = 9.1% (group 1) versus 3.7% (group 2) (p=0.041)
51. Prophylactic Cranial Irradiation
• Brain metastases are present at diagnosis in approximately 20% of
patients with SCLC.
• The brain is also a frequent site of failure after chemotherapy for
extensive disease or chemoradiotherapy for limited-stage disease.
• Several randomized trials have addressed the value of PCI following a
response to initial therapy and have consistently demonstrated a
decrease in the incidence of brain metastases.
52. • A meta-analysis reported the results of 987 patients treated in seven randomized
trials enrolling between 1977 and 1995.
• Here, 85% of these patients had limited stage and 15% extensive.
• All were randomized to either PCI or to observation following a complete
response to initial therapy.
• PCI regimens varied from 8 Gy in a single fraction to 40 Gy in 20 fractions.
• At 3 years, PCI was found to significantly decrease the incidence of brain
metastases (59% vs. 33%) and significantly improve OS (21% vs. 15%).
• There was trend toward improved brain control when PCI was administered
earlier and at higher dose.
• The publication of this study demonstrated the value of PCI in limited-stage SCLC.
• PCI in extensive-stage SCLC was specifically addressed in a more recent
randomized trial conducted by the EORTC.
53. • In this EORTC trial, 286 patients with extensive-stage SCLC were
randomized to either PCI or observation after any response to four to
six cycles of chemotherapy.
• Those assigned to the PCI arm were treated within 4 to 6 weeks of
completing systemic therapy.
• The 1-year cumulative incidence of brain metastases was significantly
decreased in the PCI arm at 15% versus 40%, and 1-year OS was
significantly increased in the PCI arm at 27% versus 13%.
• Six different PCI regimens were permitted, with biologically effective
dose ranging from 25 to 39 Gy.
54. • Despite the survival benefit reported in the Auperin meta-analysis
and the EORTC trial in extensive-stage disease, a variety of dose and
fractionation schemes were employed to treat the patients enrolled
in the trials.
• To help define the optimal dose and fractionation for PCI, a multi-
institutional intergroup trial was launched to examine standard-dose
PCI versus high-dose PCI.
55. • Patients with limited-stage SCLC who had achieved a complete
response to chemoradiotherapy were randomized to receive PCI in
standard dose, 25 Gy in 10 daily fractions, or high-dose, 36 Gy in
either 18 daily fractions or 24 twice-daily fractions.
• At 2 years, the cumulative incidence of brain metastases was not
significantly different between the two arms: 29% in the standard
dose arm versus 23% for high dose.
56. • Surprisingly, there was poorer OS in the high-dose arm: 2-year
survival was 42% in the standard dose arm versus 36% for high dose.
• This was attributed to a higher cancer-related mortality in the high-
dose arm.
• Wolfson et al recently reported the results of these assessments and
observed an increased incidence of chronic neurotoxicity at 12
months after PCI in the 36-Gy cohort (p = .02).
• Taken together, these results establish 25 Gy in 10 fractions as the
current preferred regimen to deliver PCI.
57. Chemotherapy
• The selection of chemotherapeutic agents to combine with Thoracic
RT (TRT) for patients with Limited stage SCLC is largely based on trials
of multiagent regimens used for E-SCLC.
• The currently accepted standard chemotherapy regimen for both E-
SCLC and L-SCLC is the two-drug regimen of EP (Cis + Etopo).
• SWOG was the first group to report a completed trial of concurrent
TRT with EP for L-SCLC. They reported a median survival time of 17.5
months and 4-year survival rate of 30%, which appeared superior to
the previously reported results with TRT combined with other non–
platinum-containing regimens.
58. • A recent Japanese Trial compared irinotecan and cisplatin compared
with EP for E-SCLC. The median survival was 12.8 months with
irinotecan and cisplatin compared to 9.4 months with EP (p = 0.002).
• A similarly designed SWOG Trial S0124 was unable to confirm a
survival advantage obtained by irinotecan and cisplatin.
• Hanna et al reported similarly negative findings from a third similar
Phase III trial.
• Paclitaxel has also been studied extensively in SCLC. A Phase III study
in extensive stage disease showed increased fatal toxicity without an
improvement in survival with the addition of paclitaxel to EP.
59. Role of Surgery
• A randomized trial was conducted by the Lung Cancer Study Group in
which patients with L-SCLC achieving a partial response (PR) or
complete response (CR) to chemotherapy received either resection or
none.
• There was no survival difference between the arms, with a 2-year
survival rate of 20% in both arms (p = 0.55).
• Based on this trial and on the proven survival benefit of concurrent
chemotherapy and TRT, adjuvant surgery following chemotherapy is
not recommended.
60. • There may be a role for resection in patients with stages I or II SCLC, it
is unclear that surgical intervention would provide a benefit when
compared to TRT for similar volumes or stages of disease. While it
appears that some patients may be salvaged after a PR or local
failure, resection has not been widely employed.
61. Management of Recurrent SCLC
• The prognosis of any patient with recurrent SCLC is grave, regardless
of the site of relapse. Although there are responses noted to second-
line chemotherapy, these responses are usually short-lived and often
precede rapid tumor progression. Palliative or salvage RT or re-RT
(including re-irradiating brain metastases) can be of substantial
benefit to such patients.
62.
63. Take Home Message
• Accounts for 13% of all lung cancers.
• Tobacco consumption is the most common cause.
• It is a type of round blue cell tumor.
• SIADH is the most common Paraneoplastic Syndrome.
• Patients treated concurrently has longer median survival as compared
to patients treated sequentially.
• 45 Gy in 30 fractions twice daily is better than 66 Gy in 33 fractions
once daily.
• Intracranial metastasis occur in more than 50% of patients.
64. • PCI is a Category I recommendation for patients with limited stage
disease who attain a complete or partial response.
• PCI should not be given concurrently with systemic therapy or high
dose radiation therapy.
• Optimal dose of PCI is 25Gy in 10#.
• Cisplatin + Etoposide is the most commonly used chemotherapy
regimen.
