Small Cell Lung Cancer Management

Dr.Tinku JosephDM Resident

Department of Pulmonary medicineAIMS, Kochi

INTRODUCTION

Typically arise centrally Most common presentation is a large hilar mass with

bulky mediastinal LN Common symptoms cough, SOB, wt loss. Commonly seen in smokers. Approx. 70 % with overt mets at presentation Commonly spread to liver, adrenals, bone and brain Can present with paraneoplastic syndome.

• SCLC Incidence: – 13% of all lung CA

INTRODUCTION

Natural History of SCLC

SCLC is distinguished from NSCLC by its rapid doubling time, high growth fraction, and the early development of widespread metastases

considered highly responsive to chemotherapy and radiotherapy, SCLC usually relapses within two years despite treatment

Overall, only three to eight percent of all patients with SCLC (10 to 13 percent of those with limited disease) survive beyond five years

SCLC Histology

SCLC is a “small blue round cell tumor” from neuroendocrine cells

Classifications:- oat cell (lymphocyte-like), fusiform, polygonal- OR classical, large cell neuroendocrine, combined

SCLC/NSCLC

STAGING

Staging of small cell lung cancer

STAGING

DEFINITION OF DISEASE EXTENSION

• Very-limited disease: confined to one hemithorax without mediastinal lymph node involvement.

• Limited disease: confined to one hemithorax including the contralateral lymph nodes (all within radiation field).

• Extensive disease: beyond these bounderies.

Where does SCLC metastasize to? “BALLS”

Brain (30%) Adrenal (20-40%) Liver (25%) Lung Skeleton (35%)

survival of SCLCMarginally improvement of survival in 2

decades

Limited Disease (Janne et al. Cancer 2002)

Median survival SEER database

Extensive Disease (Chute et al. J Clin Oncol 1999)

Approach to very-limited disease

Surgery followed by chemotherapy

Survival of patients with SCLC according to lymph node involvement

pTN1M0 (n=51)

pTN2M0 (n=32)

Eur J Cardiothorac Surg, 5:306;1991

pTN0M0 (n=63)

About half of patients with very-limited disease may be cured with combined-modality approach that includes surgical resection and adjuvant chemotherapy

Limited Section Disease (LS-SCLC)

Definition-: disease that is limited to the ipsilateral hemithorax and regional lymph nodes and can be encompassed in a safe radiotherapy field.

Most cases-: clinical or pathologic evidence of mediastinal lymph node disease.

For patients with LS-SCLC who have no distant metastases, no evidence of disease in the mediastinum, and no other contraindications to surgery, resection is indicated.

Followed by adjuvant chemotherapy with four cycles of cisplatin-based therapy.

Limited Section Disease (LS-SCLC)

For patients in whom surgery identifies lymph node involvement in the pathologic specimen, chemoradiotherapy is generally indicated.

For most patients with LS-SCLC who have clinical or pathologic evidence of mediastinal disease, chemoradiotherapy is indicated as the initial treatment.

Limited Section Disease (LS-SCLC)

Chemotherapy for Small Cell Lung Cancer -LS

Four cycles of chemotherapy is the mainstay of treatment for patients with LS-SCLC.

High frequency of early dissemination.

Limited Section Disease (LS-SCLC)

In addition to chemotherapy, there is a significant role for radiation therapy (RT) in the treatment of LS-SCLC.

Local tumor progression occurs in up to 80 % of such patients treated with chemotherapy alone.

High local recurrence rate can be significantly reduced by the addition of thoracic RT.

Survival is improved when thoracic RT is added to chemotherapy compared with chemotherapy alone

Limited Section Disease (LS-SCLC)

Prophylactic cranial irradiation Indicated for patients with a complete or partial

response to their initial chemotherapy treatment.

Limited Section Disease (LS-SCLC)

SCLC and symptoms of superior vena cava (SVC) obstruction, initial chemotherapy is the treatment of choice, rather than RT.

The clinical response to chemotherapy alone is usually rapid.

RT may be required for patients in extreme distress due to SVC obstruction or in those who do not respond to chemotherapy.

Limited Section Disease (LS-SCLC)

Benefit of treatment

Patients with SCLC rarely survive more than a few months without treatment, even when disease appears to be localized.

SCLC is highly responsive to both multiple chemotherapeutic drugs and radiation therapy (RT).

The results with treatment vary significantly depending upon the extent of disease.

Treated with contemporary chemoradiotherapy and prophylactic cranial irradiation-: overall response rates of 80 to 90 percent, including 50 to 60 percent complete response rates.

Median survival is around 17 months, and the five-year survival rate is about 20 percent

Benefit of treatment

CHEMOTHERAPY- LS-SCLC

Current standard of care for patients with LS-SCLC: Four cycles of combination chemotherapy (typically cisplatin plus etoposide [EP]) + concurrent thoracic radiotherapy during the early part of the chemotherapy treatment.

Prophylactic cranial irradiation (PCI) is generally recommended for patients with a complete response or significant tumor regression at the completion of chemotherapy.

Prophylactic cranial irradiation (PCI)

Chemotherapy regimens

• Etoposide + Cisplatin• standard regimen for chemotherapy in patients with

LS-SCLC along with early, concurrent thoracic radiotherapy.

• Alternative-: Etoposide + carboplatin• Neuropathy, hearing loss, renal insufficiency, CCF

Other regimens

Irinotecan-containing regimens Paclitaxel-containing regimens Novel agents Tirapazamine, thalidomide, vandetanib,

bevacizumab, matrix metalloproteinase inhibitors , tamoxifen, and the Bec2/BCG vaccine.

THORACIC RADIATION THERAPY

Improvement in survival Increase in toxicity. conventional (once daily) fractionation use doses of

approximately 60 to 70 Gy in 2 Gy fractions. Split course treatment alternating regimens of

chemotherapy and thoracic RT.

PROPHYLACTIC CRANIAL IRRADIATION

Decrease the incidence of symptomatic brain metastases and increase overall survival in patients with limited stage small cell lung cancer.

INTEGRATION WITH CHEMOTHERAPY — The addition of thoracic radiation therapy (RT) integrated with etoposide plus cisplatin (EP) chemotherapy during cycle 1 or 2 is the current standard of care for patients with LS-SCLC.

SCLC - Meta-analysis of PCI From 7 randomised trials of PCI vs no-PCI

Patients 987 (140 patients had ED-SCLC)

Chemo- & RT schemes various

Overall survival benefit +5% (95% CI: 1 -10%)

3 year survival 20 vs 15%

Incidence of brain metas 33 vs 59%

Auperin et al. NEJM 1999

Early versus late thoracic RT

conflicting data Early (starting with cycle 1 or 2 of chemotherapy)

rather than late integration of thoracic RT is associated with a better outcome.

A meta-analysis reported in 2004, A 2005 Cochrane meta-analysis, trial from the National Cancer Institute of Canada (NCIC)

Approach to SCLC - ES

SCLC - ES

The majority of patients with SCLC have extensive stage disease.

Definition-: tumor that includes distant metastases, malignant pericardial or pleural effusions, and/or contralateral supraclavicular or contralateral hilar lymph node involvement.

primary therapeutic modality is systemic chemotherapy.

Good response to chemotherapy-: RT additional benefit.

Prophylactic cranial irradiation-: decreases the incidence of symptomatic brain metastases in patients who have responded to systemic chemotherapy.

Impact on overall survival is uncertain

SCLC - ES

Cisplatin + Etoposide-: Most frequently used. Carboplatin + Etoposide Cisplatin + Irinotecan-: Favourable results Japanese Cooperative Oncology Group trial (JCOG 9511) Topotecan plus cisplatin Epirubicin plus cisplatin Three or four-drug combinations -: Added paclitaxel (not

favourable results)

SCLC - ES

• Duration of therapy-: four to six cycles of induction therapy.

• RADIATION THERAPY AFTER RESPONSE TO CHEMOTHERAPY

• Thoracic RT is associated with improved overall survival.

• Prophylactic cranial irradiation -: decrease the incidence of symptomatic brain metastases

SCLC - ES

SCLC-: In Elderly

ELDERLY PATIENTS -: one-third of patients with SCLC are 70 years of age or older.

Standard regimens-: Increased toxicity. Trials conducted -:Response rate was higher with full

doses compared with the low dose

POOR PERFORMANCE STATUS PATIENTS

No data that define the role of treatment in poor performance status patients (PS3 or PS4).

POOR PERFORMANCE STATUS PATIENTS

Median survivals in SCLC

Very-limited disease ~5 years Limited disease 18-24 months Extensive disease 10 months

SCLC without treatment < 3 months

Prognostic Factors

The host factors of poor performance status and weight loss

Stage (limited versus extensive). In extensive disease-: the number of organ sites

involved. Metastatic involvement of the central nervous

system, the marrow, or the liver is unfavorable compared to other sites.

Most trials-: women fare better than men, Presence of paraneoplastic syndromes is generally

unfavorable

Experimental Approaches- SCLC

ANGIOGENESIS INHIBITORS Oral angiogenesis inhibitors - Tyrosine kinase (TK) inhibitors

sorafenib, sunitinib, cediranib, vandetanib. Bevacizumab has been studied in combination with platinum-

based chemotherapy Topotecan, Thalidomide. IGF-1R inhibitors-: Cixutumumab IMMUNOTHERAPY Tumor vaccines anti-idiotypic antibody (BEC-2) CYTOTOXIC CHEMOTHERAPY-: Bendamustine

ACCP GUIDELINES

NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN)

NICE GUIDELINES FOR LUNG CANCER