Non small cell lung cancer medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

Stage I

Shown below is the algorithm on the treatment of the stage I non-small cell lung cancer based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

In the tumor central o peripheral?

Peripheral

Central

Is the tumor T1 or T2a?

T1ab, N0

T2a, N0

T1ab-2a, N0

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan

Does the pathological evaluation showed positive disease in the mediastinal lymph nodes?

Does the pathological evaluation showed positive disease in the mediastinal lymph nodes?

Yes

No

Yes

No

Click here for the stage III treatment

Is the tumor operable?

Click here for the stage III treatment

Is the tumor operable?

Yes

No

Yes

No

Surgical resection + lymph node dissection

Radiotherapy with stereotactic ablative radiotherapy

Surgical resection + lymph node dissection

Does the patient presents metastasis to ipsilateral peribronchial and/or hiliar nodesand intrapulmonar nodes (N1)?

Yes

No

Chemotherapy + radiation therapy

Radiotherapy with stereotactic ablative radiotherapy Adjuvant chemotherapy should be added for high-risk stages

Stage II

Stage IIA

Shown below is the algorithm on the treatment of the stage IIA non-small cell lung cancer based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

T1a-b, 2a, N1 T2b, N0 T3 Tumor larger than 7 cm (not invasive)

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan

Does the pathological evaluation showed positive disease in the mediastinal lymph nodes?

Yes

No

Click here for the stage III treatment

Is the tumor operable?

Yes

No

Surgical resection + lymph node dissection

Does the patient presents metastasis to ipsilateral peribronchial and/or hiliar nodes and intrapulmonar nodes (N1)?

Yes

No

Chemotherapy + radiation therapy

Radiation therapy with stereotactic ablative radiotherapy Adjuvant chemotherapy should be added for high-risk stages

Stage IIB

Shown below is the algorithm on the treatment of the stage IIB non-small cell lung cancer based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan Perform a brain MRI Perform a spine MRI with thoracic inlet searching for superior suculus lesions and infiltration to the subclavian vessels or spine

What is the location of the tumor?

Superior suculus tumor

Proximal airway OR Chest wall OR Mediastinum

T3 (Invasion to adjacent structures), N0

Preferred option: Surgery + pathological determination of microscopic residual tumor

Neoadjuvant Chemotherapy OR Chemotherapy + radiation therapy

Neoadjuvant chemotheerapy

Are margins from the surgical piece positive or negative for residual tumor?

Perform surgery + pathological determination of residual tumor

Surgery + adjuvant chemotherapy

Negative (R0)

Positive: Is the residual tumor microscopic (R1) or macroscopic (R2)

Are margins from the surgical piece positive or negative for residual tumor?

Adjuvant chemotherapy

Microscopic (R1)

Macroscopic (R2)

Negative (R0)

Positive (R1-2)

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy, followed or not by chemotherapy

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy

Observation

Tumor resection

Stage III

Stage IIIA

Stage IIIA: T3, N1

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan Perform a brain MRI Perform a spine MRI with thoracic inlet searching for superior suculus lesions and infiltration to the subclavian vessels or spine

Where is the tumor located?

Superior suculus tumor

Proximal airway OR Chest wall OR Mediastinum

T3 (Invasion to adjacent structures), N0

Preferred option: Surgery + pathological determination of microscopic residual tumor

Neoadjuvant Chemotherapy OR Chemotherapy + radiation therapy

Neoadjuvant chemotherapy

Are margins from the surgical piece positive or negative for residual tumor?

Perform surgery + pathological determination of residual tumor

Surgery + adjuvant chemotherapy

Negative (R0)

Positive: Is the residual tumor microscopic (R1) or macroscopic (R2)

Are margins from the surgical piece positive or negative for residual tumor?

Adjuvant chemotherapy

Microscopic (R1)

Macroscopic (R2)

Negative (R0)

Positive (R1-2)

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy, followed or not by chemotherapy

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy

Observation

Tumor resection

IIIA: T4, N0-1

Perform a pretreatment evaluation If not done, perform pulmonary function tests Perform bronchoscopy (if possible intraoperative) Perform a pathological lymph node evaluation If not done, order PET scan or CT scan Perform a brain MRI Perform a spine MRI with thoracic inlet searching for superior suculus lesions and infiltration to the subclavian vessels or spine

Is the tumor resectable?

Yes

No

Where is the tumor located?

Definitive chemotherapy

Superior suculus

Proximal airway OR Chest wall OR<br Mediastinum

Initiate neoadjuvant chemotherapy + radiation therapy

Preferred option: Surgery + pathological determination of microscopic residual tumor

Neoadjuvant Chemotherapy OR Chemotherapy + radiation therapy

Perform a surgical evaluation: Is the tumor resectable?

Are margins from the surgical piece positive or negative for residual tumor?

Perform surgery + pathological determination of residual tumor

Yes

No

Negative (R0)

Positive: Is the residual tumor microscopic (R1) or macroscopic (R2)

Are margins from the surgical piece positive or negative for residual tumor?

Tumor extraction + adjuvant chemotherapy

Definitive chemotherapy + radiation therapy

Adjuvant chemotherapy

Microscopic (R1)

Macroscopic (R2)

Negative (R0)

Positive (R1-2)

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy, followed or not by chemotherapy

Tumor resection + adjuvant chemotherapy OR Chemotherapy + radiation therapy

Observation

Tumor resection

Stage IIIB

Perform a pretreatment evaluation If not done, order PET scan or CT scan Confirmation tests of lymph node infiltration stage: Thoracoscopy and mediastinoscopy Mediastinotomy Biopsy of the supraclavicular lymph nodes Needle aspiration biopsy Endoscopic ultrasound-guided biopsy Endobronchial ultrasound-guided biopsy Perform a brain MRI

Is the tumor T1-3 or is it T4?

T1-3, N3

T4

Does the infiltration to lymph nodes meet the criteria for N3 or are there findings suggestive of metastatic disease?

Is the infiltration to the mediastinal lymph nodes contralateral or are there findings suggestive of metastatic disease?

Yes

No

Yes

No

Metastatic disease

Findings suggestive of N3

See treatment

Metastatic disease

Positive contralateral mediastinal node infiltration

Does the tumor infiltrated the ipsilateral mediastinal lymph nodes?

Click here for the treatment of metastatic disease

Definitive chemotherapy + radiation therapy

Click here for the treatment of metastatic disease

Definitive chemotherapy + radiation therapy

Yes

No

Definitive chemotherapy + radiation therapy

Click here for the stage IIIA treatment

Stage IV

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Metastatic adenocarcinoma, large cell carcinoma and not specified non-small cell carcinoma

The algorithms for the treatment of metastatic non small cell carcinoma of the lung are based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

Positive sensitizing EGFR mutation

Is pleural o pericardial effusion present (suggestive of M1a) or are findings suggestive of systemic metastasis (M1b) present?

M1b

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Perform the following tests: Perform thoracentesis and/or pericardiocenteis Perform a thoracoscopy if thoracocentesis is inconclusive

Perform the following tests: Brain MRI Bronchoscopy Mediastinal lymph node biopsy If not previously done, PET scan or CT scan

Is the liquid extracted positive for malignant cells?

Are findings suggestive of adrenal metastasis or brain metastasis?

Yes

No

Adrenal

Brain

Was the mutation discovered before the initiation of first line therapy?

Yes

No

Initiate erlotinib or afatinib

Suspend or complete chemotherapy and initiate erlotinib or afatinib OR Add erlotinib or afatinib to chemotherapy regimen

Did the tumor progress or respond?

Tumor progression

Positive response or stable tumor

Symptomatic disease

Asymptomatic disease

Systemic metastasis

Brain metastasis

Continue treatment

Multiple metastasis

Single metastasis

Multiple metastasis

Single metastasis

Continue treatment, consider local therapy

Continue treatment, consider whole brain radiation therapy

Continue treatment, consider local therapy

Consider platinum doublet with or without Bevacizumab AND/OR Erlotinib

Positive ALK mutation

Was the mutation discovered before the initiation of first line therapy?

Yes

No

Initiate crizotinib

Suspend or complete chemotherapy and initiate crizotinib

Did the tumor progress or respond?

Tumor progression

Positive response or stable tumor

Symptomatic disease

Asymptomatic disease

Systemic metastasis

Brain metastasis

Continue treatment or change to certinib according to the degree of disease

Multiple metastasis

Single metastasis

Multiple metastasis

Single metastasis

Continue treatment, consider local therapy

Continue treatment, consider whole brain radiation therapy

Continue treatment, consider local therapy

Initiate certinib OR Consider platinum doublet with or without Bevacizumab AND/OR Erlotinib

Negative EGRF and ALK or unknown mutation

What is the performance status (PS) of the patient?

0-1

2

3-4

Doublet chemotherapy OR Bevacizumab + Chemotherapy OR Cetuximab/vinorelbine/cisplatin

Chemotherapy

Supportive care

What was the tumor response to the treatment?

Progression

Positive response or stable tumor

Administer 4-6 cycles and assess progression of the disease

PS 0-2

PS 3-4

Tumor progression

Positive response or stable tumor

Initiate docetaxel or pemetrexed or erlotinib or gemcitabine

Provide supportive care

Initiate docetaxel or pemetrexed or erlotinib or gemcitabine

Continuation maintenance (cetuximab or gemcitabine) OR Switch maintenance (erlotinib or decetaxel) OR Close observation

Initiate docetaxel or pemetrexed or erlotinib or gemcitabine

Metastatic squamous cell carcinoma

What is the performance status (PS) of the patient?

0-1

2

3-4

Doublet chemotherapy OR Cetuximab/vinorelbine/cisplatin

Chemotherapy

Suportive care

What was the tumor response to the treatment?

Progression

Positive response or stable tumor

Administer 4-6 cycles and assess progression of the disease

PS 0-2

PS 3-4

Tumor progression

Positive response or stable tumor

Initiate docetaxel or erlotinib or gemcitabine

Provide suportive care

Initiate docetaxel or erlotinib or gemcitabine

Continuation mantainance (cetuximab or gemcitabine) OR Switch mantainance (erlotinib or decetaxel) OR Close observation

Initiate docetaxel or erlotinib or gemcitabine

Chemotherapeutic regimens

Shown below is a table depicting the different choices of regimens for the initial or adjuvant chemotherapy of patients with non-small cell lung cancer. The list of regimens has been adapted from the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

Cisplatin based therapy

Agent	Recommended regimen
Cisplatin 50 mg/m2 + vinorelbine 25 mg/m2	Cisplatin on days 1 and 8, vinorelbine on days 1, 8, 15, 22 and every 28 days to a total of 4 cycles
Cisplatin 100 mg/m2 + vinorelbine 30 mg/m2	Cisplatin on day 1, vinorelbine on days 1, 8, 15, 22 and every 28 days to a total of 4 cycles
Cisplatin 75-80 mg/m2 + vinorelbine 25-50 mg/m2	Cisplatin on day 1, vinorelbine on days 1, 8 and every 21 days to a total of 4 cycles
Cisplatin 80 mg/m2 + vinorelbine 4 mg/m2	Cisplatin on days 1, 22, 43, 64, then every 21 days to a total of 4 cycles, vinorelbine on days 1, 8, 15, 22, 29, every 2 weeks after day 43 until the completion of cisplatin treatmet
Cisplatin 100 mg/m2 + etoposide 100 mg/m2	Cisplatin on day 1, etoposide through days 1 to 3 and every 28 days to a total of 4 cycles
Cisplatin 75 mg/m2 + gemcitabine 1250 mg/m2	Cisplatin on day 1, gemcitabine on days 1, 8 and every 21 days to a total of 4 cycles
Cisplatin 75 mg/m2 + docetaxel 75 mg/m2	Cisplatin on day 1, docetaxel on day 1 and every 21 days to a total of 4 cycles
Cisplatin 50 mg/m2 + pemetrexed 500 mg/m2	Cisplatin on day 1, pemetrexed on days 1 and every 21 days to a total of 4 cycles

Alternative regimen: patients with comorbidities or can't tolerate cisplatin

Paclitaxel 200 mg/m² on day 1 + carboplatin area under the concentration (AUC) 6 on day 1 and then every 21 days.

Chemotherapy plus radiotherapy regimens

Chemotherapy plus radiotherapy

The list bellow show the options for concomitant chemotherapy plus radiation therapy based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

• Cisplatin 50 mg/m² on days 1, 8, 29 and 36 + etoposide 50 mg/m² through days 1 to 5 and then 29 to 33 + thoracic radiotherapy
• Cisplatin 100 mg/m² on days 1 and 29 + vinblastin 5 mg/m² weekly for 5 weeks + thoracic radiotherapy
• Cisplatin 75 mg/m² on the first day + pemetrexed 500 mg/m² on day 1 and then every 21 days to a total of 3 cycles + thoracic radiotherapy
• Carboplatin (AUC) 5 on the first day + pemetrexed 500 mg/m² on day 1 and then every 21 days to a total of 3 cycles + thoracic radiotherapy

References

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