Small Cell Lung Cancer Treatment guidelines

By

Osama Elzaafarany, MD Assistant lecturer of clinical oncology

Medical research Institute

Alexandria University, Egypt.

July 2014

• Approximately 15% of bronchogenic carcinomas.

• In the year 2013, an estimated 31.000 new cases will be diagnosed at USA.

• Nearly all cases are attributed to cigarette smoking.

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Incidence

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 Jan;63(1):11-30.

Smoking cessation: reduce risk of death in SCLC by 50%

according to ESMO guidelines

Small-cell lung cancer (SCLC) originates from

neuroendocrine-cell precursors.

Rapid doubling time, high growth fraction.

Early development of widespread metastases.

High response rates to both chemotherapy and

radiotherapy.

SCLC is the most common solid tumor associated

with paraneoplastic syndromes: SIADH, ACTH

production syndrome, and Eaton-Lambert

syndrome.

Natural history & prognosis:

Usually relapses within two years despite treatment (2ys DFS~10%), and most of patients die from recurrent disease.

Development of treatment resistance in patients with metastatic disease.

Without treatment: median survival from diagnosis is 2 - 4 months.

~ 30 % presented by limited disease.

10-15% of patients present with brain metastases and 2 year incidence after chemo-RT is 50–80%.

Median survival after recurrence ~ 4 ms.

Limited stage

Extens. stage

MS ~ 20 ms ~ 12 ms

5-ys OS ~ 25 % ~ 10 %

Response to treat. ~ 90 % ~ 70 %

Complete Response ~ 50 % ~ 20 %

Brain mets: 50 %.

Bone Mets: 40 %.

Liver mets: 25 %.

Veterans Administration Lung Study Group:

• Limited stage (LS):

disease confined to one hemithorax and

regional nodes (historically defined as fitting into

a single radiation port)

• Extensive stage (ES):

any disease not meeting limited stage criteria

Staging:

AJCC TNM staging system:

Limited stage:

Stage I-III.

Exclude: • T3-4 with multiple lung nodules.

• T3-4 with tumor/nodal volume that does not fit in tolerable radiation plan.

Extensive stage:

Stage IV.

T3-4 with multiple lung nodules.

T3-4 with tumor/nodal volume that does not fit in tolerable

Standard of care

CCRTx PCI

Limited stage

• CTx: Cis-VP16 X 4 cycles.

25Gy/10 Fx

• RTx: 45Gy/3w; (1.5Gy BID). or 60-70Gy: (2Gy/Fx).

Start Rtx. With cycle 1-2 of CTx.

Advanced stage

CTx

Evidence based medicine

Line of treatment Evidence

Why Cisplatin-VP16 ? Why not CEV?

Phase III trial from Norway. JCO, 2002

Is the concurrent CTx-RTx better than the sequential ?

Japanese Oncology Group trial, Phase III, JCO, 2002.

Why 45Gy/ 1.5Gy BID? ECOG/RTOG trial, NEGM, 1999.

PCI benefit? Meta-analysis, NEGM, 1999

• Head to head trial of Cis-Vepsid VS CAV failed to show survival advantage.

• But, it seems that Cis-VP16 is better tolerated and has good responses.

• NCCN recommend Cis-VP16 as the standard of care.

Benefit of RTx:

CTx alone VS CTx-RTx.

was shown in a 2 meta-analyses:

(Pinon et al, NEGM, 1992).

(warde et al, JCO, 1992):

5 % improvement of 2-ys OS

MS 2-ys OS 5-ys OS

Cis-VP16 15 ms 14% 5%

CEV 10 ms 6% 2%

P=0.0004

No statistical difference in toxicity

Cis-VP16 VS

CEV

Limited disease Extensive disease

Overall survival

Japanese Clinical Oncology Group trial-9104 JCO, 2002.

231 pts. Limited stage

Concurrent

Sequential

4 X EP + RTx. with first-second cycle of CTx.

4 X EP then RTx.

“RTx was 45Gy/3ws;

1.5Gy BID.”

Results: • Significant increase of MS with concurrent arm. • Increase haematologic toxicity with concurrent arm.

MS 5-ys OS Sever esophagitis

Concurrent 27 ms 24 % 9 %

Sequential 20 ms 18 % 4 %

– RTx to begin with 1st CTx cycle

– PCI given for all patients with clinical CR after completion; (25 Gy/10).

Median survival= 23 ms with twice daily VS 19 ms with once daily RTx.

5-Year OS = 26% for twice daily VS 16% in once daily .

Higher incidence of G3-4 esophagitis with twice daily

ECOG/RTOG trial, NEGM-1999

412 pts. Limited stage

Once daily

Twice daily 45Gy/ 1.5Gy BID

45Gy/ 1.8 Gy daily

Intergroup 0096

With concurrent Cis-Vepsid

P=0.04

Criticism of Intergroup 0096 trial:

“45Gy BID not biologically = 45Gy once daily.”

being tested in an ongoing randomized phase III trial (Cancer and Leukemia Group B [CALGB] 30610/RTOG 0538).

Prophylactic cranial irradiation (PCI)

• Meta-analysis: (Auperin et al, NEGM, 1999):

25 % decrease in 3-ys incidence of brain mets.

Benefit was similar in both limited and extensive stage SCLC.

Indications: • CR or PR to CCRTx. • Limited or extensive stage. ESMO-2013 guidelines when there is no progression after CCRTx.

• Recommended dose:

• 25Gy/10 Fx; (NCCN, ESMO guidelines).

• 30Gy/10 Fx

• Do not give PCI:

• Low PS.

• Age > 60 ys.

• Impaired nuero-cognitive functions.

• With CTx.

Do not give doses > 30Gy Do not give > 3Gy/Fx.

Surgery in SCLC

• Only 5% of cases.

• For Stage I: (T1-2 + N0).

• Biopsy to confirm –ve mediastinal LNs.

• Type: lobectomy.

• Adjuvant CTx is recommended after complete excision. (if –ve LNs.), add RTx to chemo If +ve LNs.

• 5 years OS= 40-60%.

• Most data are retrospective.

• Only one retrospective study by LCSG (chest, 1994) show no OS benefit, but this study had only 19% of patients with stage I !!

Irinotecan

• Irino-cis VS Cis-VP16:

Survival benefit in a Japanese phase III trial: 13 ms vs 9.5 ms (NEGM, 2002).

Failed to show survival benefit in 2 phase III American trials.

PFS improved in a meta-analysis, J Thoracic

Oncology, 2010 (not used individual pts data).

• More GI toxicity.

Role of maintenance therapy:

• Phase III trial, JCO, 2001.

• Adding Topotecan after 4-6 cycles of Cis-VP16.

• No survival benefit.

• Minor prolongation of the duration of response.

• Increase of cumulative toxicity.

Dose intensity:

• No survival benefit in randomized trials.

• Excessive treatment-related mortality.

• Meta-analysis, JCO, 1991:

Compare standard VS dose-intense CTx.

CAV and Cis-VP16.

Small insignificant increase in median survival in

extensive disease.

Avastin

• Limited Stage: Phase II.

Irino-Carbo-Avatin.

Closed early dt increase T-E fistula.

• Extensive disease: Phase II, SALUTE trial, JCO-2011.

Add to Cis/Carbo-VP16

PFS = 5.5 ms.

Ongoing phase III trial of add Avastin to CTx.

Topotecan as second line

• Topotecan VS CAV:

Phase III trial, JCO, 1999.

Same survival.

Less toxicity with Topotecan.

• Topotecan VS BSC:

Phase III trial, JCO, 2006.

Oral.

Improved OS (26 ws VS 14 ws).

• NCCN guidelines:

Category 1: relapse > 3 ms.

Category 2A: relapse < 3 ms.

Similar toxicity of Oral and IV forms.

Amrucibin

• Active relapsed and refractory SCLC (2nd line).

• Associated with common G 3-4 toxicity;

(Neutropenia).

• phase III trial, JCO, 2011 (abstract):

Compared to Toptecan as second line.

No difference in OS.

When treating metastatic disease:

Better to give Carbo-VP16.

4-6 cycles.

If CR of metastatic site, consider RTx to thorax: (ongoing CREST trial).

SCLC in elderly patients:

• Under-presented in clinical trials.

• Similar prognosis as stage-matched younger pts.

• Attention to support body systems.

• VP16 as single agent is inferior to combination CTx.

• Prefered: 4 X Carbo-VP16

Better results.

Declining renal function with aging.

AUC = 5.

Radiotherapy • High-dose volume to GTV + 1.5 cm margin.

• Include ipsilateral hilum, and bilateral mediastinum from

thoracic inlet to subcarinal region (5 cm below carina or

adequate margin on subcarinal disease).

• Exclude contralateral hilum or SCV unlessinvolved.

• If RT is preceded by chemotherapy, target volumes

should be defined on the RT planning CT scan.

However, the prechemotherapy originally involved lymph

node regions should be included.

Localized disease: