Management of Small Cell Carcinoma of Lung

Moderator: Dr R Kapoor

Department of Radiotherapy

PGIMER

Chandigarh

Introduction

Accounts for approximately 20 -15% of all lung cancers.

30,000 new cases occur in the United States each year.

Important Biological and Clinical differences from NSCLC.

Paradoxical combination of good response and high relapse !!!

Classification: WHO 1999

Primary epithelial lung cancersSmall Cell (Oat Cell Type)Non Small Cell type

Squamous Cell carcinomas

Adenocarcinomas

Adenosquamous Carcinomas

Large Cell Carcinoma

Carcinoma with pleomorphic or sarcomatoid elements

Carcinoid tumors

Carcinoma of salivary gland type

Source: Brambilla et al The new World Health Organization classification of lung tumours Eur Respir J 2001; 18:1059-1068

SCLC presents a proliferation of small cells ( 40 pack years history.Estimated 10% of heavy smokers develop lung cancer.Highest association with smoking -> Never arising in absence of a history of smoking

Clinical Features: Thoracic Disease

Local SymptomsCoughDyspneaChest PainMediastinal InvolvementHoarsenessRetrosternal Chest painVocal Cord PalsyHorner's SyndromeSuperior Vena Caval SyndromeHemoptysisPost obstructive Wheezing

Cough, Dyspnea and Chest pain are present in ~ 40 -50% patients at the time of presentation.

Recent acceleration of cough or accompanying hemoptysis increases the likelihood that an underlying cancer is present.

Chest pain is not a poor prognostic sign unless it is due to involvement of adjoining critical structures. It responds well to treatment of primary cancer.

Dyspnea may be multi factorial eg. Volume loss, atelectasis, effusions, collapse, lymphangitic spread, embolism and post obstructive pneumonia.

Post obstructive wheezing is localized unlike generalized wheezing of Br. Asthma

Hoarseness due to LRLN palsy can sometimes lead to aspiration.

Dysphagia is uncommon but when present is due to bulky mediastinal lymphadenopathy

Pleural or pericardial effusions may be present in 20 - 30% patients at presentation.

SVCO may be present in as high as 10% patients.

Hemaotogenous Metastasis

SCLC is characterized by it's propensity to spread systemically.

Usually hematogenous metastasis is the norm.

Clinical Features: Extrathoracic

Brain Metastasis:

Approximately 50% of SCLC patients develop brain metastases during the course of their disease.

Presentation varies:

Discreet ICSOL(s)

Leptomeningeal infiltration

Unlike other metastasis Brain mets are symptomatic in 90% at presentation

Clinical Features: Extrathoracic

Other Common sites of Metastasis:

Bone:

Commonly lytic lesions

Pain: Less as compared to lesions in NSCLC

No elevation in Serum ALP or Ca2+.

Adrenals / Liver:

Clinically asymptomatic mets.

However elevation in hepatic transaminases common.

Lungs:

Lymphangitis carcinomatosa: Cause of dyspnea

Paraneoplastic Syndromes

Cancer CachexiaEndocrinological SyndromesNeurological SyndromesMusculoskeletal SyndromesDermatological SyndromesHematological and VascularSIADH

Cushing Syndrome

Gynecomastia / Galactorrhea

Hyperthyroidism

Acromegaly

Eaton Lambert Syndrome

Cerebellar Degeneration

Opsoclonus-Myoclonus Syndrome

Cancer associated Retinopathy

Stiff Man Syndrome

Hypertrophic Pulm. Osteoarthopathy

Dermatomyositis

Polymyositis

Acanthosis Nigricans

Bazex disease

Erythema gyratum repens

Scleroderma

Anemia

ITP

Marantic Endocarditis

Trousseau's Syndrome

Tit-bits on some syndromes

SCLC is the most common cause of SIADH.

MC presents with Hyponatremia

Diagnostic triad of :

Euvolemia

Hyperosmalar Urine

Hypoosmolar Blood

In patients with SCLC, approximately 5% develop Cushing's syndrome MC malignancy associated with Cushing's Syndrome

Most lung neoplasms produce large amounts of ACTH precursors SCLC convert these into active ACTH (ectopic)!!

Neurological Syndromes

Overall SCLC is the most common cause.

Origin Autoimmune?

Antibodies to substances produced by tumors.

Several Types of Auto antibodies characterized:

Anti-HU (Sensory Neuropathy, Encephalomyelitis)

Anti-Yo (Cerebellar Degeneration)

Anti-Ri (Opsoclonus Myoclonus Syndrome)

Anti-VGCC (Lambert Eaton Syndrome)

Anti-Amphiphisin (Stiff Man Syndrome)

Neurological Syndromes..

Lambert Eaton Syndrome:

Proximal weakness associated with aches & stiffness.

Autonomic dysfunction dry mouth

Ptosis and opthalmoplegia milder than MG.

LEMS is usually diagnosed prior to any clinical manifestation of the tumor (2-5 yrs lag period).

2 times commoner in males

MC in ages 50 - 70 yrs.

MG

LEMS

Neurological Syndromes

Paraneoplastic cerebellar degeneration:

Abrupt onset of cerebellar symptoms

Loss of Purkinje cells.

Associated with encephalomyelitis

Sensory neuropathy:

Pseudo-obstruction of the bowel best characterized sensory neuropathy

Usually associated with SCLC.

Investigative Workup

To establish diagnosis:

FOB

FNAC

To stage the disease:

CXR

USG

CT

MRI /PET/Bone scan

To assess suitability for treatment:

Hemogram

Biochemistry : RFT

Evolution of pathological classification

Intermediate category removed due to difficulty in identification

Intermediate category proposed to indicate a continuum from SCLC to NSCLC

Gross Pathology

MC perihilar location (2/3rd) ( 65 years)

Metastatic sites: Liver, Bone marrow and bone

Cushing's Syndrome

Continued tobacco use during therapy

Increased pretreatment LDH (> 2 times increase)

CNS paraneoplastic syndromes (anti-HU antibody)

High VEGF/ bcl-2 / p -glycoprotein (MDR) expression

Based on these variables EORTC has also defined a prognostic index which includes age, performance status and serum LDH. In the high risk group the tolerance to therapy is poor as well as the survival.

Mortality during the first chemotherapy cycle was 33%

Median survival time was 133 days

2-year survival was 4.5%

Management of SCLC

Treatment Outline

SCLCStageLocalized DiseaseExtensive DiseaseRadiation Therapy (Curative intent ?)+Systemic Combination ChemotherapySystemic Combination Chemotherapy+Palliative Radiation + Palliative Care and Support

Radiation Sensitivity

Source: Radiation Biology of Lung Cancer; Sullivan et al JCB supp24

Radiation Biology

Low D0 & SF2Gy values imply the high radiosensitivity

n (extrapolation number) is also low Implies that the capacity to repair sublethal damage is limited

Low dose per fraction radiation schedules have potential here.

However due to the propensity of disseminated disease sensitivity curability

Role of 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

Dose Time Fractionation

Principle:

Alleviate the symptoms arising due to the tumor quickly.

Integrated with Chemotherapy with minimal delay

Intent of treatment decides the TDF issues

In patient with LD, good PFS and good response to CCT

30 Gy in 10# with PCI

In patient with ED or LD with poor response:

Poor PFS: 600 - 800 cGy in SF

Good PFS: 20 Gy in 5 #

Planning RT for Localized SCLC

Principles:

Adequate coverage of the 1 tumor : 1.5 2 cm

Adequate margins to account for respiratory motion

Adequate coverage of draining nodes (1st echelon) : 1 cm

Ensuring volume irradiated doesn't receive doses exceeding tolerance.

Dose:

30 Gy/10 # in 2 weeks preferred in our institution

Energy : Co60 or 4-6 MV photons

Palliative Radiotherapy

Principles:

Use high dose per fraction to achieve greatest cell kill in shortest possible time.

Use smaller number of fractions to reduce burden on facility, patient and relatives.

Use simple AP PA portal for quick, accurate and comfortable setup

Further boost RT can be tailored individually depending upon the patients response and performance status.

Dose schedules:

30 Gy in 10#

20 Gy in 5#

800 cGy in 1 #

Manual Marking

Upper lobe tumors:

Superior border is kept at the SSN

Medial border extends 3 cm across the midline on the opposite side

A field of 12 x 12 is usually used.

Lower lobe tumors:

Superior border is kept at the level of the nipple.

Supraclavicular field:

A separate supraclavicular field can be placed with a gap of 0.5 cm

Guidelines for RT planning

Upper lobe tumors:

Ipsilateral SCF should be treated

Inferior margins kept 5-6 cm below the carina

Mediastinum should be taken into the field with 1 cm margins

A margin of 2 cm given around the primary tumor

Lower lobe tumors:

Lower border should encompass the lower border of mediastinum down to the level of the diaphragm

Gross mediastinal adenopathy is taken into the field but SCF can be avoided

Portal arrangements

Upper Lobe

Middle Lobe

Lower lobe

Critical organs and doses

Results of Thoracic RT

Landmark trial by the MRC in UK(Miller et al 1969):

144 patients selected fit for radical Sx or RT

Mean survival was 23.5 weeks for Sx and 43 weeks for RT (p = 0.03)

5 yr survival 1% in the Sx group and 5% in the radiation alone group

Sole survivor in the Sx arm had received RT.

in and in the 80sa new debate emerged among the oncologist as to whether radiotherapy was really required in the management of small-cell carcinoma following results from several small randomized trials. These trials had shown that median survival was in the range of 12 -15 months with CCT alone and that radiation did not add to an improved survival. The controversy could only be settled in 1992 with the advent of 2 large meta-analysis

Results

Effect of palliative RT

Changing Paradigms of Rx

Paradigm 1 : Surgery as Standard TreatmentParadigm 2 : Thoracic radiation better than SurgeryParadigm 3 : Thoracic Irradiation with adjuvant Chemotherapy Paradigm 4 : Combination chemotherapy with adjuvant Radiotherapy Paradigm 5 : Integrated Chemotherapy and Radiation therapy

RT results

2 yr survival

2 yr local control

Is TRT needed?

Warde et al (JCO, 1992):

11 RCTs (published) included

Total patients 1911

Looked at 2 yr survival, local control and toxicity

Found that:

Overall benefit of adjuvant RT on OS is 5%

LC rate improved by 25.3%

1.2% increased chance of death due to Rx related toxicities

Is TRT needed

Pignon metanalysis (NEJM , 1992):

Used updated patient data from investigators

Based on 2140 patients

Assessed 3 yr survival rates and prognostic factors for survival

14% reduction in the mortality rates at 3 yrs

Absolute benefit in OS of 5.4%

Twice as better local control (48% vs 23%)

Survival difference greater for patients aged < 50 yrs.

Is TRT needed

Both meta-analysis have conclusively proved:

Addition of thoracic RT improves the OS by approximately 5%

Reduces the risk of intrathoracic failures by 30% - 60%.

In addition both meta-analyses used trials prior to the CE era so a more effective therapy has not been evaluated.

The increased incidence of toxicity related deaths is significantly reduced with modern Rx.

Conclusion: Addition Thoracic Radiation is definitely indicated in Limited Stage SCLC both to improve LC and OS

?? Controversies ??

Ideal treatment volume?

TDF issues

Sequencing with CCT

Role of PCI

Ideal Volume

Deciding the treatment volume

Controversies

How much of mediastinal / hilar nodes to be taken ?

Whether supraclavicular nodes are to included?

Whether volume of irradiation is to pre-CCT volume or post CCT volume?

Optimum portal design?

Intrathoracic Volume Incorporation

Perez et al : Reported on results of SECSG on treatment of SCLC using thoracic RT (1981)

69% of patients treated with inadequate portals had intra thoracic failures (w.r.t. 32.5% treated with adequate portals)

Inadequate portals failure to include contralateral hilum or mediastinum

Data from While J et al Impact of Radiation therapy quality control in LC in SCLC

Conclusion: Failure to include opposite mediastinal and hilar nodes in the treatment volume can lead to significant intrathoracic failures

In the study conducted by White et al on patients enrolled in the SWOG 7628 protocol, major protocol variations were found in 44 of 140 patients and in them :

Stastically poorer survival

Significantly higher intrathorac failure rates

Similar results have been reported Mantyla et al who found that ITR was 60% in patients with inadequate RT as compared to 20% in pts. with adequate RT

Results from:

Perez CA, Krauss S, Bartolucci AA el ul. Thoracic and elective brain irradiation with concomitant or delayed multiagent chemotherapy in the treatment of localized small cell carcinoma of the lung. Cancer 1981; 47 2407-13

JOEL E. WHITE, MD; TIMOTHY CHEN. PHD et al The Influence of Radiation Therapy Quality Control on Survival, Response and Sites of Relapse in Oat Cell Carcinoma of the Lung. Cancer 1982;50 :1084-90

Post CCT or Pre CCT volume?

21/5/1977

6/7/1977

26/8/1977

11/10/1977

26/10/1977

22% of patients who had failed in the chest had failed in the treatment site

MC causes of chest failures were pleural effusions or peripheral masses in the ipsilateral lung

Although 50% patients had distant mets after failures most common cause of deterioration of health was the intrathoracic failures.

Mira and Livingstone recommended that the pre-CCT volume is of vital importance and at least 50% - 66% of the radiation dose should be delivered to this volume to eliminate microscopic disease.

In this study conducted under the SWOG marginal recurrences contributed significantly to intrathoracic failures and decreased survival.

Pre CCT vs Post CCT volume

Patients treated to the post-CCT tumor volume have equivalent survival

51 weeks survival with pre CCT vol w.r.t. 46 weeks survival with post CCT vol (SWOG study ; Kies et al JCO 1987)

Patients treated to pre CCT volumen will have same local control rates

More than 80% of local failures were within the post CCT irradiated volume (Brodin et al Acta Oncologica 1990)

Patients treated to the pre-CCT volume can have significant pulmonary toxicity if they survive

Double incidence of pnuemonitis and leucopenia in patients treated to pre-CCT volumes.(SWOG study ; Kies et al JCO 1987)

Some studies have found a lower CR rate in patients treated to pre CCT volume (? artifact)

Conclusion: It is safe to irradiate only the post CCT volume.

Portal Design

Simple AP PA fileds are gold standard for irradiation of SCLC

Customizing fields not usual as:

Most of the tumors are situated centrally so majority of peripheral lung parenchyma can be avoided.

Customizing field apertures may result in tumor miss

Majority of major protocol violations in the study by white et al were due to inappropiate shielding

Difficulty in compensating for complex respiratory motion

Customization probably too time consuming an effort for patients who are unlikely to be cured

Conclusion: Customized portal designing is unlikely to add to control

Time, Dose & Fractionation

Dose and Fractionation of Radiation

Dose, time and fractionation choice depend upon:

Tumor size and bulk

Nature of symptoms

Severity of symptoms

Patient performance status

Expected survival

Possibility of complications

Logistical factors

Patient supportive care available

Dose of Radiotherapy

NCI reported a clear dose response:

25 Gy in 10 #

37.5 Gy in 15 #

Higher dose associated with a significant gain in PFS

Arrigada et al did a trial on LD with 3 dose schedules given by split course:

45 Gy: 5 yr survival 16%

55 Gy: 5 yr survival 16%

65 Gy: 5 yr survival 20% (p = N.S.)

BED of 30 Gy in 10# is 39 for tumor control BED of 37.5 Gy in 15# is 46 for tumor control

Altered Fractionation

Conclusion: Altered fractionation with split course is not effective

Why is altered fractionation with split course not effective?

The reason may lie in the fact that the SCLC cells are most fast dividing of all malignant cell types of the lung cancer. The timing of the break to allow delivery of Chemotherapy after the break and the healing of toxicities also allows repopulation of a more resistant clone of cells.

Continuous AF schemes

Conclusion: Sadly Continuous AF is too toxic for routine use !!!

Sequencing with CCT

Sequencing with CCT

Several techniques of sequencing possible:

Concurrent

Sequential

Alternating

Controversies that exist are:

Is concurrent better than the other models

What is the ideal time of giving RT with CCT

CRT protocols

Concurrent:

Radiation is started along with 1st CCT cycle typically between the D1 or D2 of CCT.

CCT administered as scheduled.

Weekly chemoradiation is not used as full therapeutic doses of CCT need to be delivered.

Sequential:

RT is administered after completion of 3 -4 cycles of chemotherapy. CCT is not delivered during RT

Additional cycles of CCT may be given after RT

Alternating:

RT is usually given in a split course and CCT is administered between the treatment breaks.

Concurrent vs Sequential CCT

Generally 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

Why not Concurrent CRT?

Controversy still exists about relative superiority of CCRT

Impairment in delivery of both modalities a frequent problem

Most of patients will present with ED

Even patients with LD will 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

Alternating Chemoradiation

Popularized in the 1980s due to the toxicity of then available CCT agents precluding concomitant / sequential approach

Largest trial by Gregor et al (ECOG/LCCG)1997 (n = 349)

Poor local control and severe acute hematotoxicity in the study arm

Most patients failed within the portal

Conclusion: Alternate CRT is inferior to sequential CRT

Early vs Late Thoracic RT

Early better:

Reduce chances of systemic metastasis

Reduce chances of appearance of chemoresistant clones

Lower probability of radioresistance

Diminished accelerated repopulation

Late Better:

Allows shrinkage of portals to a reduced tumor volume

Reversible resistance (Kinetic and epigenetic resistance.)

Timing of RT

The NCI trial reported by a Murray et al was able to show a significant improvement in survival of patients treated with early thoracic radiation which was delivered concurrently with the first cycle of EP regimen. in this study, the chemotherapy regimen used was alternating CAV with EP x 3 eachSimilarly the trial reported by Jeremic et all from Yugoslavia showed an improvement in both the survival, as well as in the local control with or a early concurrent chemoradiationSimilarly the Japanese Oncology group has also the most rated a significant improvement in the overall survival and the local control of patients treated with early concurrent chemoradiation.However the other trials failed to show any significant improvement with the use of early RT as compared to Late RT

Timing of RT

Two meta-analyses have also been published on this topic:

Fried et al:

Defined late RT as after 9 weeks after starting CCT

OS benefit of 5% at 2 yrs with early RT (p = 0.03)

Benefit with the use of Platinum based regimens only and with the use of hyperfractionated regimens

Cochrane review:

Early RT defined as that started within 30 days of CCT

No significant benefit at 2 or 3 yrs with the use of early or late CCT

But found a significant advantage in 5 yrs survival with the use of early thoracic radiotherapy with the use of cisplatin based CCT ; OR of 0.62 (p = 0.02)

Timing of RT

Conclusion: Early Start of RT does lead to a better outcome

Role of PCI

Role of PCI

Dr Heine Hansen suggested possible role of PCI in 1973 extrapolating experience from Leukemias

Role believed to exist as:

SCLC has aggressive behavior like leukemia

It is very chemosensitive

Development of new CCT regimens in 70's lead to increased expectations of cure

Development of brain mets was thought to be the most important cause of failures if chemotherapy was to be successful.

BBB was expected to be a impediment for disease eradication from the CNS (sanctuary)

Benefit from PCI

In order for PCI to be integrated with the regimen it should fulfill certain basic requirements:

Solitary CNS relapse should be a significant clinical problem

Systemic control should be maintained for a prolonged period of time

Side effects from PCI should not overcome any survival benefit

PCI should be effective in eliminating sub clinical metastatic disease in the CNS

Demonstrable survival benefit should be present

Meta-analysis

A meta-analysis was published in BMC by Meert et al (2001)

12 trials included; 1547 patients

5 trials evaluated the role of PCI in patients who had attained CR

5 trials included only LD stages

The 1st figure shows the hazard ratio of impact of PCI in terms of time to relapse in the brain with a significant HR of 0.48 in all patients. This corresponds to a reduction in risk of brain mets from approx 20% to 6%The 2nd figure shows the impact of PCI on the survival of patients who were in CR with a significant HR of 0.82Similar results have also been reported in an earlier meta-analysis by Arrigada et al (1999) where the improvement in patients with CR after CCT. Here also a HR of 0.84 was identified which corresponded a improvement of 5% improved survival at 3 yrs.

Toxicity of PCI

Long term neurological toxicity difficult to evaluate

Jhosnson et al reported on 20 patients with median F/U of 6 yrs

15 of 20 patients had some neurological complaints and abanormalities

Another study by Laukkanen et al reported memory loss in 60% of long term survivors of SCLC who had received PCI

The issue of increased toxicity remains difficult to evaluate as the patients dont live long enough to manifest any toxicity. As such small case series only exist. In these the interpretation is difficult due to multiple confounding variables like effect of chemotherapy, alcohol, tobacco, aging and paraneoplastic syndromes.

Practice Guidelines

PCI should be given in:

Patients with LD stage with radiological CR

Documented absence of brain mets ( pre PCI CT)

Good performance status to merit further treatment

Dose of PCI:

20 - 24 Gy in 10 12 # is the recommended dose schedule

Timing:

Should be administered 2-3 weeks after completion of chemotherapy

How given:

Parallel opposing fields with energy of 4-6 MV / Co60

Summary

Ideal RT volume:

Incorporate B/L mediastinal nodes

Post CCT volume can be irradiated safely

Extensive portal customizations can backfire

TDF issues:

Conventional once daily RT is of choice

Integration with CCT:

Early start of RT is better

Concomitant CRT is more effective but also highly toxic

Role of PCI:

Can improve survival in small subgroup of patients

Chemotherapy

Chemotherapy

The chemosensitivity of SCLC was first identified 50 years ago with the recognition that CCNU could effect tumor regression in 50% patients

Several agents have single agent activity

However:

Complete remissions are relatively infrequent

Remission durations tend to be brief

Combination therapy is known to produce superior survival**

These results are based on the results from large cooperative group trials conducted in the 1970s.

Single Agent Chemotherapy

Standard CCT regimens

Cisplatin based CCT

CE is considered standard regimen.

CR rates

20-45% in LD

10-25% in ED

ORR 60- 70%

Median survival 10 12 months

Carboplatin is equivalent in therapeutic efficacy as shown by a HCOG study (Median survival 11.8 months with ORR of 70 -80%)

Cisplatin and etoposide have been considered as the standard CCT regimen after 2 randomized trials comparing PE vs CAV and CAV/PE showed that:

no difference in response rates

no difference in median survival

less myelosuppression, neurotoxicity, and cardiac toxicity

The results from the Hellenic Cooperative Oncology group have been instrumental in the acceptance of CE as a less toxic alternative to PE regimen.

Alternative CCT regimens

Single agent Topotecan:

One phase III trial reported by Shiller et al compared Topotecan to CAV (n = 188)

Same ORR (21% & 15%) and survival (5.8 & 5.5 mo)

Better symptom control however greater hematological toxicity

However it has also been shown in a RCT by same author that 4 cycles of Topotecan after 4 cycles of PE is not superior to observation.

Conclusion: Single agent Topotecan fails to improve results over those obtained by PE regimen in SCLC when used as 1st line approach

Schiller, JH, von Pawel, J, Clarke, P, et al (1997) Preliminary results of a randomized comparative phase III trial of topotecan (T) versus CAV as second-line therapy of small cell lung cancer (SCLC) [abstract 41]. Lung Cancer 18(suppl1),13-14

Alternative Chemotherapy

The trial by Richardet et al had evaluated responses in limited stage disease and extensive stage diease separately

Combination CCT

Active regimens yield objective response rates in the range of 80% to 90%

Complete remissions occurring in 30 to 50% of patients

Median survival:

7 to 9 months in extensive-stage patients (3 yr OS ~ 1%)

20 months in patients with limited disease.(3 yr OS ~ 20%)

Best survival is achieved in good performance status patients who present with limited-stage disease and who receive combined modality therapy with chemotherapy plus thoracic radiotherapy.

Toxicity of CCT

Most common complication is severe myelosuppression, which occurs in 25% to 30%

Rates increased to 75% with CRT

Cyclophosphamide-based therapy associated with the highest incidence of neutropenia

Cisplatin plus etoposide generally represents the least myelosuppressive regimen

Late complications (heard of but not seen!!)

Pulmonary fibrosis

Cardiac toxicity

More intensive CCT

The concept of MDTI is analogous to that of TCP/NTCP

It defines the maximum tolerated dose intensity

dose intensity refers to dose in mg/m2/week

The plateauing of the curve is important

Because of lack of significant improvement in the survival rates with the use of CCT attempts have been made to improve the efficacy of CCT.This is believed to be due to ab initio resistance to CCT (resistance present before CCT was administered).

Alternative Strategies

Dose intensification

Weekly Chemotherapy

Alternating Chemotherapy

Dose intensification

Conclusion: Dose intensification by 25 50% over the standard doses fails to improve the survival but increases toxicity significantly

Weekly Chemotherapy

Conclusion: Dose intensification by giving weekly CCT fails to improve the survival but increases toxicity significantly

CODE regimen consists of cisplatin (25 mg/m2 for 9 consecutive weeks); vincristine (1 mg/m2 weeks 1, 2, 4, 6, 8); doxorubicin (40 mg/m2 weeks 1, 3, 5, 7, 9); and etoposide (80 mg/m2 days 13, weeks 1, 3, 5, 7, 9).This regimen is completed in 9 weeks rather than the standard 18 weeks and results in two fold increase in dose intensity of the 4 agents used.

Alternating CCT

3 major trials have appeared:

Fukuoka et al (JNCI 1991)

Roth et al -SECSG (JCO 1992)

Evans et al NCI (AIM 1987)

All the 3 trials failed to show any significant advantage of alternate CAV/EP vs EP alone but did show that CAV alone was inferior. (OS with CAV/EP 16.8 mo, EP alone 11.6 mo and CAV 8.0 mo)

Conclusion: Alternating non cross resistant CCT regimens failed to improve results as compared to standard regimens

Chemotherapy for recurrence

Selected patients may be treated provided:

Good performance status

Symptomatic relapse

Local control maintained

Time of relapse > 6 months

Desires further treatment

Response rates:

Vinorelbine: 14%

Irinotecan: 33%

Topotecan: 19%

Paclitaxel: 25%

SVCO in SCLC

SVCO

Seen in 6-10% patients at presentation

60 -70% of the patients are non ambulatory with poor performance scores

60- 70% have extensive disease

60 -70% have extrathoracic extension of disease

80% patients have moderate to severe SVCO

20% will die within 2 weeks of presentation

Management of SVCO

Principle:

SVCO is a oncologic urgency but a medical emergency.

The 1st goal is hemodynamic stabilization of the patient to allow the patient to lie down in the treatment couch.

Radiotherapy should be given in large doses per fraction as:

Fast debulking is needed

Most patients have poor general condition cant tolerate fractionated regimens

Patients are suitable for palliative treatment alone.

Management of SVCO

Step 1: Initial workup

Patient should be nursed in a sitting position as most have orthopnea with Type I hypoxia

Anxiety allayed through proper explanation and medications

To alleviate respiratory distress:

Moist O2 inhalation high flow

Nebulization with agonists + Steroids: Reduces bronchospasm

Injectable Deriphyllin: Reduces bronchospasm

Injectable loop diuretics: Reduce edema, promotes diuresis and relieves pulmonary congestion

Injectable steroids: Reduces airway edema.

Injectable antibiotics: In event of fever of significant cough

Management of SVCO

Step 2: Monitoring

Regular checking of

Pulse

BP

Respiratory rates

Arterial O2 saturation (where available)

Patient assessment:

Reduction in edema

Ability to lie down

Reduced respiratory distress

Biochemical and hematological evaluation

Radiological assessment of disease as permitted by patient's condition

Management of SVCO

Further management in the event of the HP S/O SCLC can be:

Chemotherapy

Radiotherapy

Chemotherapy can be used initially in patients who are:

Young

Good performance status

Good response to medical therapy

XRT planned as a adjuvant in the subsequent treatment.

Radiotherapy in SVCO

Position: Supine with head turned to opposite side

Superior border: Encompasses the ipsilateral SCF upto the crico-thyroid junction

Inferior border: Taken 2 -4 cm below the carina

Medial border: 1 cm beyond the mediastinal shadow on opposite side

Lateral border: 1.5 -2 cm margin from the lateral most extent of tumor

Doses:

800 cGy in single fraction

2000 cGy in 5 fractions

3000 cGy in 10 fractions least commonly used

Response to RT

Radiotherapy in SVCO

Radiotherapy alone can result in:

Immediate subjective improvement (< 3 d) in 60% patients of SCLC

Early improvement in 90% patients

70% patients will respond to RT alone

Addition of CCT doesn't improve response or survival

CCT by itself results in a slight delay in response

Investigational Agents

Matrix Metalloproteinase Inhibitors (Marimastat)

Important in cancer cell invasion, metastasis, and angiogenesis.

Two phase III studies

NCI and EORTC

No difference in survival

Adversely impacted the quality of life

Tyrosine Kinase Inhibitors: (Imatinib mesylate)

Phase II study

19 patients treated : No observed responses !!

Tyrosine kinases (TKs) are enzymes associated with transmembrane growth receptors.

C-Kit is a growth receptor that appears to have a role in SCLC proliferation.

c-kit expression in 70% of patients with SCLC

Imatinib has shown growth inhibition of SCLC cell lines, and this inhibition correlates with inhibition of c-kit TK

Other agents

Antibody based therapy

Anti sense BCL-2 oligonucleotide (Genasense)

BCL-2 inhibits apoptosis and might contribute to chemotherapy resistance.

Anti sense oligonucleotides inhibit the translation of mRNA

Rudin treated 12 patients with refractory SCLC

No objective responses were observed

2 of the 12 patients had stable disease.

Follow up Goals

To detect symptomatic* progression of disease.

Gathering outcome data

Providing reassurance and psychological support.

No evidence for an improved outcome from early detection of an asymptomatic recurrence

No evidence that more intense follow-up improved any outcome

Follow up Goals

To detect symptomatic* progression of disease.

Gathering outcome data

Providing reassurance and psychological support.

No evidence for an improved outcome from early detection of an asymptomatic recurrence

No evidence that more intense follow-up improved any outcome

Follow Up Protocol

History and Physical Examination*:

Every 3 months for 1 -2 years

Every 6 months for the next 5 years

Annually thereafter

Investigations Suggested:

Chest X-rays

Other expensive investigations are not cost effective.

Follow up: Other Issues

Detection of residual disease is not required after complete radiological response to 1 therapy due to lack of effective Rx in this scenario.

Smoking cessation useful in the small subset who get complete response:

Can potentially delay recurrence

Can reduce 2nd cancers

Conclusions

Despite its sensitivity to radiation SCLC is extremely frustrating to treat

The systemic nature of disease and fast growth make it one of the most aggressive malignancies known

Radiation therapy is an important part of the therapeutic armamentarium

Systemic combination chemotherapy is the mainstay of treatment but ineffective in the long run.

Thank You

TrialYearRegimenORRMedian SurvivalToxicitiesCommentsSouhami et al (CRC UK) (n = 438)1994Weekly ID /CE 82%10.8 moDose intensity relatively more in 3 weekly armCAV/ EP alt 3 weekly81%10.6 moNCI / SWOG (n = 219)1999CODENA9% mortality in the CODE arm.CAV/EP standardNANCI / SWOG (n = 227)1994CODE + G-CSF84%12 months19%3% patients in CODE arm died due to toxicityCAV/ EP Standard77%11 months8%

???Page ??? (???)09/03/2007, 05:24:34Page / DrugDoseORRSurvivalToxicityCyclophosphamide1- 1.1g/m212 -23% 17 weeksMyelosuppressionIfosfamide1.2- 1.5 g/m250%43 weeksTransient confusion, hemorrhagic cystitisDoxorubuicin60-75 mg/m250%26 weeksCardio-pulmonary toxicity, additive effect with RTVincristine1.5 mg/m240-50%Peripheral neuropathyVindesine3-4 mg/m220-33%Vinorelbine25-30 mg/m210-20%Cisplatin60-120 mg/m25-30%Nephrotoxicity, emesis, neurotoxicityCarboplatin300-400 mg/m260-80%ThrombocytopeniaEtoposide300-400 mg/m220-50%Nausea, myelosuppressionTeniposide300 mg/m230-50%Nausea, myelosuppressionPaclitaxel250 mg/m230%43 weeksIrinotecan100 mg/m247%Life threatening diarrrheaTopotecan1.5-2 mg/m240%20-25 weeksGemcitabine1g/m227%12 months

???Page ??? (???)09/03/2007, 05:24:35Page / RegimenDrugsDoseFrequencyEPCisplatin25 mg/m2 D1 33 weeklyEtoposide100 -120 mg /m2 D 1- 3EP (oral)Cisplatin100 mg/m2 D14 weeklyEtoposide oral50 mg PO D1 21CECarboplatin300 mg/m2 D14 weeklyEtoposide120 mg/m2 D 1 3IEIrinotecan70 mg/m2 D1, 8, 154 weeklyEtoposide80 mg/m2 D1 3CAVCyclophosphamide1 g /m2 D13 weeklyAdriamycin40 mg/m2 D1Vincristine1 mg /m2 D1CAECisplatin50 mg/m2 D13 weeklyAdriamycin45 mg/m2 D1Etoposide50 mg/m2 D1 5ICEIfosfamide1.2 g/m2 D1 43 weeklyCisplatin20 mg/m2 D1 4Etoposide75 mg/m2 D1 4V- ICEVincristine1 mg D154 weeklyIfosfamide5000 mg/m2 D1Carboplatin300 mg/m2 D1Etoposide120 mg/m2 D 1,2 Oral 240 mg/m2 D3

???Page ??? (???)09/03/2007, 05:24:35Page / TD 5/5 Volumes & Tolerance (Gy) Organ 1/3rd 2/3rdwholeLung 453017.5Heart 604540Esophagus 605855Spinal cord 5047Brachial plexus 626160

???Page ??? (???)09/03/2007, 05:24:35Page / SymptomFrequencyImprovedComplete ReliefCough61 93 %56 -65%30 54%Hemoptysis31 47% 81 -86%74 -82%Dyspnea50 54%-37 -40%Pain42 57%65- 74%50 -52%Atelectasis23 26%-60 -62%Hoarseness20 - 25%-50 -52%Dysphagia5 10%-

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Second niveau de plan

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Kryberg et alWHOIASLCWHO

19621967198119881999

Oat cellLymphocyte LikeOat CellSmall Cell Cancer

PolygonalIntermediatePolygonalFusiformMixed small / large cellOthersCombinedCombined small / large cell

???Page ??? (???)09/03/2007, 05:24:35Page / RADIOGRAPHIC FEATURE SQ. CELL (%) ADENOCA (%) SCC (%) LARGE CELL (%)Nodule 4 cm 14462118Peripheral location 29652661Central location 6457442Hilar/perihilar mass 40177832Hilar adenopathy 38196132Mediastinal adenopathy 591410

???Page ??? (???)09/03/2007, 05:24:35Page / Lambert-Eaton Syndrome Myasthenia gravisMuscle strength maximum contraction delayed decreasing during ongoing exerciseOcular muscles paresis rare typicalAutonomic nervous system anti-cholinergic syndrome normalTendon reflexes reduced with post-tetanic faciliation normalSingle nerve stimulation reduced amplitude normal amplitudeRepetitive stimulation additional increment at 20-Hz decrement at 3-Hz stimulation

???Page ??? (???)09/03/2007, 05:24:35Page / LiverAdrenalBoneKidneyBrainPancreas

Limited Stage0.3760.3160.3090.1360.3240.08

Extensive Stage0.7350.260.560.160.3730.174

Nodal Involvement

Mediastinal0.49

Hilar0.78

PointVALSG DefinitionISALC DefinitionLimitation One Hemithorax One HemithoraxLocal Extensions? Allows if can be encompassed in one RT portal X Does not defineRegional NodesX Nodes not defined but included if encompassed in one RT portal Both ipsilateral and contralateral mediastinal and hilar nodes included in the definitionSupraclavicular Nodes Only ipsilateral allowed Both ipsilateral and contralateral allowedIpsilateral pleural effusionX Not defined ? Allowed ? Allowed irrespective of cytological positivity

???Page ??? (???)09/03/2007, 05:24:35Page / GroupExampleD0 (Gy)n

IClassic SCLC0.76 -1.241.0-2.0

IILarge Cell / Variant SCLC0.76-1.54.6-17.7

IIIAdenocarciniomas1.0-1.41.2-6.8

???Page ??? (???)09/03/2007, 05:24:35Page / GroupRadiation protocolCCTLocal ControlSurvivalTurrisi et al (1999) ECOG / RTOG / SWOG45 Gy in 25 # in 5 weeks (n= 206) with concurrent CCT in 1st week4 x EP D1 -D3 x 3weekly36%18% (5 yr)45 Gy in 30# over 3 weeks giving 2 fractions /day (n = 216) with concurrent CCT4 x EP D1 -D3 x 3weekly52%26% (5yr)Bonner et al (2000)50.4 Gy in 28# over 5 weeks with 2 cycles concurrent EP (n = 132)3 x EP (NA) > 1 x EP (Adj)66%34% (3 yr))48 Gy in 32 # over 3 weeks with 2 fractions per day and gap of 2 weeks after 1st 16#s (n = 130)3 x EP (NA) > 1 x EP (Adj)65%29% (3 yr)

???Page ??? (???)09/03/2007, 05:24:35Page / TrialYearRegimenORRMedian SurvivalToxicitiesCommentsJhonson et al (SECSG) (n = )198700%CAV escalated (65%)63%29.3 weeks79%CAV standard53%34.7 weeks40%Hong et al (n = 353))198900%CAV escalated (Cyclo 2g)31%41 weeksNAIn LD stage only and established superiority of CEVCEV standard42%58 weeksNACAV standard38%55 weeksNAIhde et al 199400%EP standard85%12 months2%Escalated by giving for 5 days EP escalated 81%11 months25%

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