Adenocarcinoma of the lung medical therapy

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

Medical Therapy

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

stereotactic ablative radiation therapy

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

stereotactic ablative radiation therapy 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)?

If lymph node extension is detected initiate neoadjuvantchemotherapy + radiation therapy

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 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

Stage III

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

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 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 cancer

Definitive chemotherapy + radiation therapy

Click here for the treatment of metastatic cancer

Definitive chemotherapy + radiation therapy

Yes

No

Definitive chemotherapy + radiation therapy

Click here for the stage IIIA treatment

Stage IV

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

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

M1a

M1b: solitary site systemic metastasis

Perform the following tests: Perform thoracentesis and/or pericardiocentesis 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

Local therapy Ambulatory catheter drainage Pleurodesis Mediastinal window PLUS Therapy for metastatic disease (click here for the treatment of metastatic cancer)

Treat according to tumor stage: I II III

Perform a needle aspiration biopsy for metastasis confirmation

Surgical resection + adjuvant radiation therapy Radiation therapy alone: stereotactic ablative radiation therapy + Whole brain radiation therapy OR stereotactic ablative radiation therapy PLUS Pathologic evaluation of surgical piece and lymph nodes

If the lung disease is curable, administer local therapy for the adrenal lesion: Surgical adrenal resection OR Radiation therapy OR Administer therapy for metastatic disease in case of not curable lung lesions (click here for the treatment of metastatic cancer)

What is the TN stage of the lung tumor?

T1-2, No-1 T3, N0

T1-2, N2 T3, N1-2 N3, regardless of the T stage T4 regardless of the N stage

Surgical resection of lung tumor + adjuvant chemotherapy OR Neoadjuvant chemotherapy + surgical resection or stereotactic ablative radiation therapy OR Stereotactic ablative radiation therapy

Administer therapy for metastatic disease in case of not curable lung lesions (click here for the treatment of metastatic cancer)

Local or Regional Recurrence

• The algorithm bellow shows the approach for a local or regional recurrence of a non small cell lung cancers are based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

What is the site of the recurrence?

Bronchial obstruction

Mediastinal lymph node

Superior vena cava obstruction

Severe hemoptysis

Resectable tumor

Surgical correction of the obstruction: laser therapy, stent or any other surgical procedure OR Radiation therapy (external-beam or brachytherapy) OR Photodynamic therapy

Has the patient received radiation therapy?

Chemotherapy + radiation therapy OR External-beam radiation therapy OR Superior vena cava stent collocation

Surgery OR Radiation therapy (external-beam or brachytherapy) OR Laser therapy, photodynamic therapy or tumor embolization

Tumor resection (preferred option) OR Radiation therapy (stereotactic ablative radiation therapy or external-beam radiation therapy)

Yes

No

Administer systemic therapy (Click here for the treatment of metastatic disease)

Administer chemotherapy + radiation therapy

Are findings suggestive of disseminated disease present?

Yes

No

Click here for the treatment of metastatic disease

Observation OR Click here for the treatment of metastatic disease

Metastatic Cancer

Medical Therapy for Metastatic Non Small Cell Lung Cancer

• 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.

What the specific subtype according to the specific histological characteristics of the tumor?

Adenocarcinoma Large cell carcinoma of the lung Not specified non-small cell lung cancer

Squamous cell carcinoma

Is the patient a smoker or former smoker?

Yes

No

Perform specific EGFR and ALK mutation testing: What is the specific mutation?

Perform specific EGFR and ALK mutation testing: Is there a mutation in any of those genes present?

Yes

No

Sensitizing EGFR mutation

ALK mutation

Negative EGFR and ALK

Click here for the squamous cell carcinoma specific treatment

Click here for the sensitizing EGFR mutation specific treatment

Click here for the specific therapy for the ALK mutation specific treatment

Click here for the treatment of negative sensitizing EGFR and ALK mutation metastatic disease

Metastatic Adenocarcinoma, Large Cell Carcinoma and Not Specified Non-Small Cell Carcinoma

• The algorithms for the treatment of metastatic adenocarcinoma, large cell carcinoma and not specified non small cell carcinoma of the lung are based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

Positive Sensitizing EGFR Mutation

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 based chemotherapy with or without Bevacizumab AND/OR Erlotinib

If findings suggestive of progression of the disease are present, click here for the third line therapy

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 based chemotherapy with or without Bevacizumab AND/OR Erlotinib

If findings suggestive of progression of the disease are present, click here for the third line therapy

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

If findings suggestive of progression of the disease are present, click here for the third line therapy

Third line therapy

• The algorithm below shows the third line therapy for metastatic disease according to the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

What is the performance status of the patient?

PS 0-2

PS 3-4

If not previously used, administer any of the following: Docetaxel Erlotinib Gemcitabine Pemetrexed

Administer erlotinib or provide suportive care

What is the performance status of the patients after the treatment?

PS 0-2 (stable tumor)

PS 3-4 (tumor progression)

Provide supportive care or try experimental treatments

Provide supportive care

Multiple Lung Cancers

• The algorithm for the treatment of multiple non small cell lung cancers are based on the 2014 NCCN Non-Small Cell Lung Cancer guidelines.

Is there suspicion of multiple lung cancers?

Yes

No

Perform the following tests: If not previously done, PET scan or CT scan Contrast chest CT Brain MRI

Administer treatment according to the TNM stage of the tumor

Is the disease is confined to the chest or is there systemic proliferation?

Disease confined to the chest

Systemic proliferation

Assess the mediastinal lymph nodes in order to determine the N stage of the tumor

Click here for the treatment of systemic metastasis

What is the N stage of the tumor?

N0-1

N2-3

Is the patient symptomatic?

Click here for the treatment of systemic metastasis

Yes

No

Is the lesion a solitary nodule or are there multiple nodules?

Solitary nodule

Multiple nodules

What is the risk of turning into a symptomatic disease?

High

Low

Is definitive local therapy possible?

Observation

No

Yes

Consider palliative chemotherapy with or without local Radiation therapy

Administer one of the following treatments: Preferred option: Parenchymal sparing resection Radiation therapy Ablation therapy

Click here for the treatment of systemic metastasis

Go to the appropriate algorithm according to the characteristics of the disease: local or regional recurrence or metastasis

References

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