limited-stage small cell lung carcinoma: overview with focus on management

Limited-Stage Small Cell Lung Carcinoma: Overview with Focus on Management

John M. Watkins, M.D.

Medical University of South Carolina

Department of Radiation Oncology

Background

Small Cell Lung Cancer 15-20% of primary lung neoplasms

• Decreasing incidence

Classically large, central mass Rapid growth High metastatic potential (liver, adrenals, bone,

bone marrow, brain).

Classification

WHO (old classification) Oat cell Intermediate cell Combined oat cell (with SqCC or adenoCA)

WHO/IASLC (1999) Classical SCLC (most common) Large cell neuroendocrine Combined small-cell (predominant SCLC with

areas of NSCLC)

Histopathology

Diagnosis by light microscopy often sufficient: Small “blue” malignant cells Sparse cytoplasm Finely dispersed chromatin without nucleoli High mitotic rate, necrosis common

Histopathology

ImmunohistologyEpithelial

• keratin

• epithelial membrane Ag

Neuroendocrine* • NSE

• chromogranin A

*Pre-requisite for dx of large cell neuroendocrine but not small-cell.

Genetic Features

p53: mutated in 75-90% 9p LOH: 90% Rb: loss of transcripts (60%) or

abnormal gene product (40%) Telomerase: activated in 90% c-kit: up-regulated in 80-90% k-ras: mutation rare (unlike NSCLC)

Staging

VA Lung Study GroupLimited (60-70%): primary/nodal

disease confined to ipsilateral hemithorax, within a single radiotherapy port

Extensive (30-40%): metastatic disease outside the ipsilateral hemithorax

IASLC: Limited (M0) vs extensive (M1)

Lung Cancer 2002;37:271

Work-Up

H&P Chest, liver, adrenal CT

Adrenal 17% FN rate by CT Head MRI (or CT)

CNS mets in 20-30% overall; 15% detection in asymptomatic pts

Bone Scan +/- Marrow Bx

Involved in 15-30% at presentation, but solitary metastatic focus in only 2-6%

Am J Roentgenol 1983;140:949 J Neurooncol 2000;48:243Cancer 1989;63:763

Work-Up

Role of PET (and PET/CT)Not presently reimbursable for staging

SCLCSmall retrospective studies at present:

• 4-11% upstaged

• Management change in ~15%

• RT nodal coverage changed in 25%

Clin Lung Cancer 2008;9:30 Radiol Clin N Amer 2007;45:609

Work-Up

Tissue DiagnosisTrans-Bronchial vs CT-Guided

ApproachCore Biopsy vs FNAPleural Effusion

Prognostic Factors

Performance Status Weight Loss Stage

Early Limited > Limited > Extensive Within extensive, number of involved sites

LDH (elevated = adverse) Gender (women>men) Paraneoplastic syndrome (adverse)

Treatment Paradigm

InterventionsSurgery (early)ChemotherapyRadiotherapySurgery (recent)

Outline

Background Classification Histopathology Genetic Features Staging Review Work-Up Prognostic Factors

Management Early Studies Chemotherapy Radiotherapy Surgery

SHAMELESS PLUG

Limited Stage SCLC: Early Role of Surgery

1960s: MRC (n=144, randomized)Limited-Stage: Resection vs RT

• Minimal active chemotherapy at the time

Similar poor outcomes (1-yr surv ~20%) Resection out of favor with improvements

in chemotherapy, advancements in radiotherapy

Lancet 1973;2:63

Limited Stage SCLC:Chemotherapy Due to systemic nature of SCLC, chemotherapy

is considered an essential intervention SCLC is very chemo-responsive, with response

rates 80-90% for limited stage; however, very rarely sustained (median 6-8 months) Upon recurrence, median survival 4 months cCR ~50% in limited stg, ~15-25% extensive stg

cCR controversial prognostic indicator; pooled European trial data suggests cCR and KPS were independent predictive factors for survival >2yrs

Cancer 2000;89:523

ChemotherapyRegimens Cisplatin / Etoposide (EP)

Demonstrated equivalent survival to CAV (or CEV) chemo or EP/CAV alternation in extensive stage disease

• EP/RT superior survival to VEC/RT in limited-stage

Most clinicians favor EP in order to avoid adriamycin-associated toxicities concurrent with XRT

JCO 1992;10:282 JNCI 1991;83:855 JCO 2002;20:4665

Limited-Stage SCLC:Radiotherapy

Why XRT? ~80-90% eventual local failure with chemo alone cCR may improve long-term survival… so add RT to boost

cCR rates CALGB (Perry; n=399)

ChemoRT (cyc 1) vs ChemoRT (cyc 4) vs Chemo Chemo = cyclophos/etoposide/vincristine q3wk x18mo

(adria replaced etoposide every other cycle after cycle 6) RT = 40 Gy to primary, mediast, bilat s-clavs + 10 Gy

boost (also PCI to all pts, concurrent w/chemo) Results: ChemoRT regimens improved cCR, FFF, OS

NEJM 1987;316:912


META Analysis (Pignon, 13 randomized trials): 2103 evaluable patients, mdn survivor f/u 43 months Improved survival of 5.4% at 3yrs for chemoRT over

chemo alone.• Benefit more apparent in younger patients (RR 0.72 for age

<55y vs 1.07 for >70y) Unable to discern benefit of “early” (w/in 60 days of

chemo start) vs “late” RT initiation, or sequential vs concurrent.

NEJM 1992;327:1618


Timing of XRT: JCOG 9104 (Takada): 231 pts w/LS-SCLC Concurrent vs Sequential:

• Cis/Etopo q3-4wk x4cyc, 45 Gy @ 1.5 Gy/fx BID w/cyc 1 vs after cyc 4

Trend improved survival for concurrent chemoRT• Median Surv: 27.2 vs 19.7 months (p=0.097)• Increased leukopenia in concurrent, similar esophagitis

JCO 2002;20:3054


Timing of XRT: META Analysis (Huncharek): 1574 evaluable patients, 7 of 8 trials used platinum-based

chemo regimen (3 cisplatin-etoposide alone) Evaluation of 1-, 2-, and 3-year overall survivals of patients

treated with early (cycle 1-2) vs late (>3 cycle, or sequential, or split) radiotherapy concurrent with chemotherapy.

Outcome: Early initiation results in 50-60% relative improvement in 3-year survival

Oncologist 2004;9:665


Radiotherapy Dose / FractionationPresent Acceptable Regimens

• Daily: 50 – 70 Gy @ 2 Gy/fx once daily

• BID: 45 Gy @ 1.5 Gy/fx twice daily

• Concomitant Boost: 61 Gy @ 1.8 Gy/fx, BID over final 9 days


Rationale:Linear cell kill even at low doses

• No shoulder = minimal DNA repair capability

Pilot studies demonstrate efficacy & tolerability of BID chemoRT

• 2y OS - 40%

• Gr 3 esophagitis: ~35-40%

Smaller fraction size should spare late toxicity


NEJM 1999;340:265


Design: Limited Stage SCLC Chemotherapy: Cisplatin (60 mg/m2) + Etoposide (120

mg/m2), q3wks x 4 cycles Radiotherapy: 45 Gy delivered @ 1.8 Gy/fx daily (5 wks)

versus 1.5 Gy/fx BID (3 wks)

• RT begins with cycle 1

• Fields: gross tumor, ipsi hilar, bilat mediast• Ipsi S-clav only if clinically involved

• Inf border ~5cm below carina (or ipsi hilum); otherwise, 1-1.5cm to block edge

• Megavoltage linacs only (no Cobalt)

• PCI (whole brain) given 25 Gy @ 2.5 Gy/fx if cCR

Limited Stage SCLC: BID vs Daily RT

Eligibility SCLC limited to one hemithorax +/- ipsi s-clav No pleural effusion (regardless of cytology) Bone scan, bilat BM bx neg Labs: plt (>100k), WBC (>4k), Cr (<1.5) FEV1: >1L

Stratification ECOG 0-1 vs 2 Gender Wt loss past 6 mo (<5% vs >5%)

Limited Stage SCLC: BID vs Daily RT Enrollment

No Major differences Majority ECOG PS 0-1 Rare s-clav at pres’n Majority whites Majority <5% wt loss


Toxicity Higher Gr 3 esophagitis

for BID, o/w no diff

Limited Stage SCLC: BID vs Daily RT Clinical Response Rate

No difference between BID / QD

Limited Stage SCLC: BID vs Daily RT Outcomes

At mdn f/u 8y (min 5y)

• 5y OS 26% BID vs 16% QD

Patterns of Failure• Thoracic failure

~35% BID vs ~50% QD• Local + Distant

~5% BID vs ~25% QD Subgroup Analysis

• Worse PS & malegender assoc with

worse px

Limited Stage SCLC: BID vs Daily RT Issues:

Increased toxicity• Requirement of elective mediastinal nodal radiotherapy?• Identifiable factors associated with severe esophagitis?

Suboptimal local control • Was 45 Gy in daily fractionation a sufficient comparative

arm?• Increased thoracic failures in QD arm

• Reduction of thoracic failure is primary benefit of XRT; with chemo alone, ~90% local failure!!

• Benefit of higher dose?• Benefit of increased dose intensification?

• Other treatment-related factors impacting loco-regional control in BID group?

Limited Stage SCLC: RT Volume Role of Elective Nodal RT (De Ruysscher)

Phase II Study (prospective) RT Targets: Primary Tumor & +LNs (by CT)

• 45 Gy @ 1.5 Gy BID (w/cyc 1-2)• Carbo/etopo chemo x5cyc

At median f/u 18 months, isolated nodal failure in 3/27 (11%)

• All ipsilat supraclav! None mediastinum• Grade 3 esophagitis in 8/27 (30%)• “The safety of selective nodal RT… should not be

extrapolated to patients with LD-SCLC until more data are available”

Radiother Oncol 2006;80:307

Limited Stage SCLC: Limited Stage SCLC: EsophagitisEsophagitis

Predictors of Severe Acute Esophagitis from Predictors of Severe Acute Esophagitis from Twice-Daily Thoracic Radiotherapy and Twice-Daily Thoracic Radiotherapy and

Concurrent Chemotherapy for Concurrent Chemotherapy for Small-Cell Lung CancerSmall-Cell Lung Cancer

John M. Watkins, M.D.John M. Watkins, M.D.Medical University of South CarolinaMedical University of South CarolinaDepartment of Radiation OncologyDepartment of Radiation OncologyCharleston, South Carolina, U.S.A.Charleston, South Carolina, U.S.A.

Oral presentation at the 90th Annual Meeting of the American Radium Society, Laguna Niguel, California: 3 May 2008. Manuscript submitted to Int J Radiat Oncol Biol Phys, 13 Jun 2008.

ObjectivesObjectives

In SCLC patients undergoing twice-daily RT In SCLC patients undergoing twice-daily RT with concurrent platinum-based with concurrent platinum-based chemotherapy, describe:chemotherapy, describe:– Severe Acute Esophagitis (RTOG Grade Severe Acute Esophagitis (RTOG Grade >>3)3)

IncidenceIncidence

Treatment Delays (attributable to toxicity)Treatment Delays (attributable to toxicity)

Associated Factors (Patient-, Tumor-, Treatment-, and Associated Factors (Patient-, Tumor-, Treatment-, and Dosimetric-Related)Dosimetric-Related)

DesignDesign

Retrospective cohort descriptive seriesRetrospective cohort descriptive series– Medical University of South CarolinaMedical University of South Carolina– Ralph H. Johnson Veterans’ Affairs Medical Ralph H. Johnson Veterans’ Affairs Medical

Center (Charleston, SC)Center (Charleston, SC)

DesignDesign

Inclusion Criteria:Inclusion Criteria:– Limited- or Extensive-Stage SCLCLimited- or Extensive-Stage SCLC– Concurrent chemoRT with twice-daily RT at 1.5 Concurrent chemoRT with twice-daily RT at 1.5

Gy per fractionGy per fraction– Completion of Completion of >>42 Gy42 Gy– CT-based treatment planning (3D reconstruction)CT-based treatment planning (3D reconstruction)– Treatment conducted at MUSCTreatment conducted at MUSC

DesignDesign

Exclusion Criteria:Exclusion Criteria:– Treatment break >5 days (unless due to Treatment break >5 days (unless due to

esophageal toxicity)esophageal toxicity)Machine maintenance, holidays considered treatment Machine maintenance, holidays considered treatment breaksbreaks

– RT at another institution/facilityRT at another institution/facility– Insufficient post-chemoRT follow-upInsufficient post-chemoRT follow-up

Minimum 3 months post chemoRT completionMinimum 3 months post chemoRT completion

MethodsMethods

Retrospective analysis of QA DatabaseRetrospective analysis of QA Database– June 1999 through June 2007June 1999 through June 2007

DefinitionsDefinitions– Severe Acute EsophagitisSevere Acute Esophagitis: RTOG Grade : RTOG Grade >>33

Grade 3Grade 3: Severe odynophagia requiring feeding : Severe odynophagia requiring feeding tube, intravenous fluids, hyperalimentation, tube, intravenous fluids, hyperalimentation, +/- +/- >15% weight loss>15% weight loss

Grade 4Grade 4: Complete esophageal obstruction, : Complete esophageal obstruction, ulceration, fistula, or perforationulceration, fistula, or perforation

Grade 5Grade 5: Death due to esophagitis: Death due to esophagitis

http://www.rtog.org/members/toxicity/acute.htmlhttp://www.rtog.org/members/toxicity/acute.html

MethodsMethodsDefinitions & StatisticsDefinitions & Statistics– Stepwise univariate logistic regression analyses Stepwise univariate logistic regression analyses

of potential associated factorsof potential associated factors– Secondary multivariate analysis for significant & Secondary multivariate analysis for significant &

marginally significant factors (multiple logistic marginally significant factors (multiple logistic regression model)regression model)

MethodsMethodsDefinitions & StatisticsDefinitions & Statistics– Variables analyzed:Variables analyzed:

Elective mediastinal Elective mediastinal irradiationirradiationDays RT start to Days RT start to completioncompletionEsophageal volumeEsophageal volumeMean esophageal doseMean esophageal doseEsophageal Dosimetry Esophageal Dosimetry (Relative Volume)(Relative Volume)

– Area Under Curve Area Under Curve – Dose Thresholds Dose Thresholds

(V5(V5V45)V45)

Age (Age (<</>65yrs, />65yrs, continuous)continuous)

GenderGender

RaceRace

Tobacco Use (Active)Tobacco Use (Active)

Tumor SiteTumor Site

Tumor Size (Max; Tumor Size (Max; <</>3cm, />3cm,

continuous)continuous)

Number of beamsNumber of beams

Study PopulationStudy PopulationPatient CharacteristicsPatient Characteristics– 48 patients included; median post-RT survivor 48 patients included; median post-RT survivor

follow-up 25.8 months (range 2.7-83.0)follow-up 25.8 months (range 2.7-83.0)

n %

AgeMedian(Range)

% >70 yrs

63.5 yrs(47-82)

14 29.2

GenderMale 64.6% 31 64.6

RaceWhite 89.6% 43 89.6

Active Tobacco Use

19 39.6

Study PopulationStudy PopulationTumor CharacteristicsTumor Characteristics

n %

Primary Tumor Location*

RightLeft

2221

51.248.8

Primary Tumor Size$

Median(Range)

4.5cm(1-11)

*Of 43 patients, excluding 2 mediastinal primaries and 3 with indeterminate *Of 43 patients, excluding 2 mediastinal primaries and 3 with indeterminate location by records.location by records.$$By maximal dimension, of 41 patients with recorded data.By maximal dimension, of 41 patients with recorded data.

nn %%

Hilar Lymph Hilar Lymph NodesNodes

IpsilateralIpsilateralBilateralBilateral

414133

85.485.46.36.3

Mediastinal Lymph Mediastinal Lymph NodesNodes

IpsilateralIpsilateralBilateralBilateral

262688

54.254.216.716.7

Supraclavicular Supraclavicular Lymph NodesLymph Nodes

IpsilateralIpsilateral 66 12.512.5

Study PopulationStudy PopulationRadiotherapy CharacteristicsRadiotherapy Characteristics

n %

Number of Beams

345

6*

162291

33.345.818.82.1

Field Volume$

IL MediastBL Mediast

IL SClavBL SClav

8632

16.712.56.34.2

nn %%

RT DaysRT DaysMedianMedian(Range)(Range)

22 days22 days(18-34)(18-34)

RT DelayRT DelayMedianMedian(Range)(Range)>>4 days4 days

22(1-10)(1-10)

2323

77

47.947.9

14.614.6

RT Dose CompletedRT Dose CompletedMedianMedian(Range)(Range)

45 Gy45 Gy(42-51)(42-51)

*Initiated RT with AP/PA, changed at ~9 Gy to 6-field.*Initiated RT with AP/PA, changed at ~9 Gy to 6-field.$$IL=ipsilateral, BL=bilateral, Mediast=mediastinum, SClav=supraclavicular.IL=ipsilateral, BL=bilateral, Mediast=mediastinum, SClav=supraclavicular.

Study PopulationStudy PopulationChemotherapy CharacteristicsChemotherapy Characteristics

nn %%

Regimen*Regimen*CECE

CbECbE12123636

12.212.287.887.8

Cycles*Cycles*MedianMedian(Range)(Range)

>>4 cycles4 cycles

44(2-6)(2-6)

3636 87.887.8

*Of 41 pts with chemo data; CE=cisplatin/etoposide; CbE= *Of 41 pts with chemo data; CE=cisplatin/etoposide; CbE= carboplatin/etoposide. Prior to concurrent therapy, one patient received carboplatin/etoposide. Prior to concurrent therapy, one patient received paclitaxel with CbE for 3 cycles and another changed from CbE after 1 cycle of paclitaxel with CbE for 3 cycles and another changed from CbE after 1 cycle of CE.CE.

Study PopulationStudy PopulationDosimetric CharacteristicsDosimetric Characteristics– 47 patients with contoured esophageal 47 patients with contoured esophageal

volumes and mean/maximal esophageal volumes and mean/maximal esophageal dosesdoses

EsophagusEsophagus nn=47=47

VolumeVolumeMedianMedian(Range)(Range)

39.3 cc39.3 cc(10.3-123)(10.3-123)

DoseDoseMeanMean

(Range)(Range)MaximumMaximum

(Range)(Range)

19.7 Gy19.7 Gy(5.3-30.8)(5.3-30.8)45.6 Gy45.6 Gy

(27.1-51.4)(27.1-51.4)

Study PopulationStudy PopulationDosimetric CharacteristicsDosimetric Characteristics– 38 patients with dose-volume histograms.38 patients with dose-volume histograms.

Relative Volume

Median Range

V5V10V15V20V25V30V35V40V45

58.8%54.5%52%

47.2%45.8%40.8%37%33%8%

(28-90%)(25-84%)(3-81%)

(0.5-79%)(0-78%)(0-77%)

(0-75.5%)(0-73%)(0-58%)

ResultsResultsAcute ToxicitiesAcute Toxicities– All 48 patients evaluableAll 48 patients evaluable

RTOG Grade

<2 3 4-5

Esophageal37

(77.1%)11

(22.9%)0

(0%)

Pulmonary46

(95.8%)1

(2.1%)1

(2.1%)

ResultsResultsUnivariate AnalysisUnivariate Analysis

OR p-value 95% CI

Gender 0.353 0.1388 0.0889-1.402

Race 0.825 0.8699 0.083-8.251

Age* 1.027 0.4718 0.955-1.104

Age >65 1.971 0.3280 0.506-7.682

Tobacco Use 0.492 0.3471 0.112-2.157

Tumor Laterality

1.5 0.7388 0.138-16.269

Tumor Size 1.204 0.1865 0.914-1.584

Tumor Size >3cm

5.474 0.1291 0.609-49.710

Number of Beams

0.880 0.7989 0.328-2.359

OR p-value 95% CI

Mediastinal Coverage

1.543 0.5514 0.370-6.426

RT Time 0.953 0.7065 0.743-1.222

Dose 0.888 0.9938 0 - >100

Esophageal Volume

0.987 0.5223 0.949-1.027

Mean Esophageal Dose

1.003 0.0017 1.001-1.005

Maximal Esophageal Dose

1.000 0.7152 0.998-1.003

RV-AUC*# 1.304 0.0037 1.090-1.559

*Continuous variable. *Continuous variable. #RV-AUC=Relative Volume-Area Under Curve.RV-AUC=Relative Volume-Area Under Curve.

ResultsResultsMultivariate AnalysisMultivariate Analysis– Only RV-AUC remained significant:Only RV-AUC remained significant:

OR p-value 95% CI

RV-AUC 1.303 0.0037 1.090-1.559

ResultsResultsAssociation of Relative Volume by Association of Relative Volume by Absolute Dose ThresholdAbsolute Dose Threshold

Grade 0-2 Grade 3 p-value OR* 95% CI

V5 0.49 0.72 0.0052 3.179456 1.390-7.275

V10 0.43 0.67 0.0038 3.497436 1.471-8.317

V15 0.41 0.65 0.004 3.691932 1.488-9.157

V20 0.375 0.62 0.0039 3.098413 1.417-6.777

V25 0.345 0.59 0.0042 2.935947 1.383-6.231

V30 0.33 0.57 0.0053 2.310791 1.266-4.217

V35 0.305 0.551 0.0043 2.349635 1.292-4.274

V40 0.275 0.525 0.004 2.469511 1.318-4.629

V45 0.06 0.115 0.1192 1.474251 0.896-2.426

0% vs 48% 0% vs 48% for V15 for V15 </</>>50%50%

*Odds ratio for a change of 10% (of patients experiencing grade 3 toxicity).*Odds ratio for a change of 10% (of patients experiencing grade 3 toxicity).

ConclusionsConclusions

Twice-daily thoracic radiotherapy at 1.5 Gy Twice-daily thoracic radiotherapy at 1.5 Gy per fraction with concurrent chemotherapy is per fraction with concurrent chemotherapy is associated with ~25% risk of severe acute associated with ~25% risk of severe acute esophagitis (RTOG grade 3).esophagitis (RTOG grade 3).

Relative volume dosimetric parameters were Relative volume dosimetric parameters were statistically significantly associated with statistically significantly associated with grade 3 toxicity.grade 3 toxicity.– V15 as suggested surrogate within present V15 as suggested surrogate within present

series. series.

Limited Stage SCLC: Limited Stage SCLC: FractionationFractionation

Survival Comparison of Dose-Optimized Survival Comparison of Dose-Optimized Once Versus Twice-Daily Radiotherapy Once Versus Twice-Daily Radiotherapy

with Concurrent Chemotherapy for with Concurrent Chemotherapy for Limited Stage Small-Cell Lung CancerLimited Stage Small-Cell Lung Cancer

John A. Fortney, M.D.John A. Fortney, M.D.Medical University of South CarolinaMedical University of South CarolinaDepartment of Radiation OncologyDepartment of Radiation OncologyCharleston, South Carolina, U.S.A.Charleston, South Carolina, U.S.A.

Poster presentation at the 90th Annual Meeting of the American Radium Society, Laguna Niguel, California: 3 May 2008. Manuscript in progress for submission to Lung Cancer.

MethodsMethods

Single institution retrospective cohort comparison of Single institution retrospective cohort comparison of limited-stage SCLC patients treated with curative-intent limited-stage SCLC patients treated with curative-intent concurrent chemoradiotherapy. concurrent chemoradiotherapy.

Compare toxicity and survival outcomes of BID RT to 45 Compare toxicity and survival outcomes of BID RT to 45 Gy at 1.5 Gy per fraction vs QD RT to >59 Gy at 1.8-2 Gy Gy at 1.5 Gy per fraction vs QD RT to >59 Gy at 1.8-2 Gy per fraction. per fraction.

Overall survival comparison between the two RT cohorts Overall survival comparison between the two RT cohorts (log-rank test). (log-rank test).

Patients received all RT at a single institution with Patients received all RT at a single institution with concurrent platinum-based chemotherapy. concurrent platinum-based chemotherapy.

ResultsResults

Between 1994 and 2007: Between 1994 and 2007: – 72 limited-stage SCLC patients were identified for inclusion into the 72 limited-stage SCLC patients were identified for inclusion into the

present studypresent study55 treated with twice-daily (BID) RT 55 treated with twice-daily (BID) RT

17 treated with once-daily (QD) RT 17 treated with once-daily (QD) RT

– Treatment groups balanced by patient, tumor, and treatment Treatment groups balanced by patient, tumor, and treatment characteristics.characteristics.

ResultsResultsAt a median survivor follow-up of 22.9 months (range 5.7-84.9), 40 At a median survivor follow-up of 22.9 months (range 5.7-84.9), 40 patients have died. patients have died.

Estimated 1-, 2-, and 3-year overall survivals for the entire population at Estimated 1-, 2-, and 3-year overall survivals for the entire population at were 76.4%, 46.0%, and 38.9%, respectively, with a median survival of were 76.4%, 46.0%, and 38.9%, respectively, with a median survival of 22.7 months. 22.7 months. – No statistically significant difference in overall survival was detected No statistically significant difference in overall survival was detected

between the BID and QD cohorts (median 22.7 vs 22.2 months, between the BID and QD cohorts (median 22.7 vs 22.2 months, respectively; p=0.603 by log rank). No difference DSS, FFF, LRFFF.respectively; p=0.603 by log rank). No difference DSS, FFF, LRFFF.

ConclusionsConclusions

The present retrospective cohort comparison did The present retrospective cohort comparison did not detect a statistically significant difference in not detect a statistically significant difference in overall survival, disease-specific survival, freedom overall survival, disease-specific survival, freedom from failure, or loco-regional freedom from failure from failure, or loco-regional freedom from failure between patients receiving BID RT to 45 Gy vs QD between patients receiving BID RT to 45 Gy vs QD RT to >59 Gy with concurrent chemotherapy. RT to >59 Gy with concurrent chemotherapy.

While BID RT remains a proven standard, further While BID RT remains a proven standard, further prospective study of higher-dose and/or dose-prospective study of higher-dose and/or dose-intensified RT is warranted.intensified RT is warranted.

Limited Stage SCLC: BID vs Daily RT Ongoing investigations:

CALGB 30610

CONVERT• Cis/Etopo (25/75 mg/m2, d1-3) q4wk x4-6cyc• RT: init d22 (cyc 1)

• 45 Gy BID vs 66 Gy QD

• Accrual Target: 532


Limited-Stage SCLC: Role of Surgery

Limited Stage SCLC: Role of Surgery Renewed interest in resection for

solitary pulmonary nodule (SPN) SCLC4-12% of SPNs~4% of SCLC presents as SPN, more

likely to be variant histology Impressive survival in pooled analysis of

resected SPN SCLC: 5y OS 40-53%Majority received post-rsxn chemotherapy

Chest 1992;101:225

Limited Stage SCLC: Role of Surgery

Mayo Clinic (n=77)Pneumonectomy (2), bilobectomy (3),

lobectomy (28), sublobectomy (34), hilar bx (10)

Mediastinal LND (50), sampling (19)At mdn f/u 19mo, 5y OS 38% for stage I-IIPost-op chemo (3) or chemoRT (40)

Mayo Clin Proc 2006;81:619


Induction ChemoRsxn (n=260, review of 9 trials)Chemo Response ~90%60% of pts went to resection

• Complete resection in 80% of these (50% overall)

pCR in 10% (majority with some residual)5yr OS ~70% for pT1N0 disease

Comp Text Thorac Oncol W&W;Baltimore 1996:439


Induction ChemoRsxn (n=328, LCSG)CAV x 5cyc, then re-stage & randomize:

• Resection + RT & PCI

• RT & PCI

66% response; 146 pts randomized:• 70 rsxn (58 attempted rsxn, 54 completed)

• 76 no rsxn

No difference survival (2yr OS ~20%)

Chest 1994;106;(6 suppl):320S

A bit about PCI…

Role of Prophylactic Cranial XRT Incidence of CNS Mets

~50% for all SCLC; as high as 80% at 5y post-Tx Elective PCI (WBRT) decreases risk to <5% Meta Analysis showed 5% survival benefit @ 3y Typical dose 30-35 Gy @ 2-2.5 Gy/fx

• Ongoing RTOG 0212 trial comparing:• 25 Gy @ 2.5 Gy/fx daily

• 36 Gy @ 2 Gy/fx daily

• 36 Gy @ 1.5 Gy/fx BID

Prophylactic Cranial Irradiation

Meta analysis demonstrated ~5% OS benefit at 3y in pts with CR

Prophylactic Cranial Irradiation

Survival Benefit: 3y OS 20% PCI vs 15% no PCI

NEJM 1999;341:476

limited-stage small cell lung carcinoma: overview with focus on management

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