Small Cell Carcinoma of Lung
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Transcript of Small Cell Carcinoma of Lung
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%-
???Page ??? (???)09/03/2007, 05:24:35Page /
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Second niveau de plan
Troisime niveau de plan
Quatrime niveau de plan
Cinquime niveau de plan
Sixime niveau de plan
Septime niveau de plan
Huitime niveau de plan
Neuvime 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%
???Page ??? (???)09/03/2007, 05:24:35Page /