lung%20cancer
LUNG CANCER
Lung cancer is having a malignant tumor in the lungs especially in the cells lining air passages.
Primary tumor-related signs and symptoms are cough, dyspnea, hemoptysis, and chest discomfort.
Signs and symptoms due to intrathoracic spread may involve the nerves (hoarseness, dyspnea, muscle wasting of upper limb, Horner's syndrome), chest wall and pleura (chest pain, dyspnea) and vascular structures (facial swelling, dilated neck veins, cardiac tamponade) & viscera (dsyphagia).
The signs and symptoms due to metastatic spread are bone pain with or without pleuritic pain, neurologic symptoms, limb weakness, unsteady gait, cervical lymphadenopathy, and skin nodules.

Pharmacotherapy

Adjuvant Therapy for Non-Small Cell Lung Cancer (NSCLC)
  • Neoadjuvant or adjuvant therapy, given concurrently with radiation therapy depending on the disease stage, is recommended for high-risk patients with stage IB-IIIA
Chemotherapy for Stage IB-IIIA High-risk Patients
  • Cisplatin-based regimens (Cisplatin plus either Vinorelbine, Etoposide, Gemcitabine, Docetaxel, or Pemetrexed) are recommended
    • Cisplatin + Pemetrexed combination is preferred in patients with nonsquamous NSCLC
  • Carboplatin-based regimens (Carboplatin plus either Paclitaxel, Gemcitabine or Pemetrexed) are recommended for patients with comorbidities or with contraindications to Cisplatin therapy
    • Combination with Pemetrexed is preferred in patients with nonsquamous NSCLC
Immunotherapy
  • Durvalumab therapy is recommended for patients with unresectable stage III NSCLC as consolidation therapy after chemoradiation
Systemic Therapy for Non-Small Cell Lung Cancer (NSCLC)
  • Recommended in patients with advanced, metastatic, or high-risk early resectable disease [ie high risk stage IB patients (with poorly defined tumors, vascular invasion, wedge resection, minimal margins, >4 cm tumor, visceral pleural involvement, and regional LN that cannot be assessed) with negative nodal margin, stage IB patients with positive nodal margin, or patients with stage IIA, IIIA, IIIB, or IV irregardless of nodal margin status]
  • Selection of systemic therapy is based on the histology of NSCLC
    • Histologic subtype and molecular testing should be determined before therapy so that the best treatment can be selected
  • Targeted therapy is potentially very effective in patients with specific gene mutations or rearrangements, and in patients with metastatic disease
  • Platinum-based chemotherapy lengthens survival, improves symptom control and offers better quality of life
    • No specific platinum-based regimen is superior to the other

First-line Therapy

Recommended Combination Regimens for Advanced or Metastatic NSCLC or NSCLC NOS with PS 0-1       
  • Pembrolizumab-based regimens
    • Preferred regimen if without contraindications to Pembrolizumab 
    • Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin combination is the preferred regimen for patients with adenocarcinoma, large cell, NSCLC NOS with PS of 0-1
    • Pembrolizumab + Carboplatin or Cisplatin + Paclitaxel or albumin-bound Paclitaxel combinations are the preferred options for patients with squamous cell NSCLC with PS of 0-1
  • Atezolizumab + Carboplatin  + Paclitaxel + Bevacizumab combination may be used for patients with adenocarcinoma, large cell, NSCLC NOS
  • Bevacizumab-based regimens (Bevacizumab + Pemetrexed + Carboplatin or Cisplatin, Bevacizumab + Carboplatin + Paclitaxel) are only recommended for patients with adenocarcinoma, large cell, NSCLC NOS
    • Criteria for receiving Bevacizumab + chemotherapy: Nonsquamous NSCLC and absence of hemoptysis
    • Bevacizumab should be given until disease progression but should be used cautiously in patients with risk of thrombocytopenia and bleeding
  • Carboplatin-based combinations (Carboplatin plus either albumin-bound Paclitaxel, Docetaxel, Etoposide, Gemcitabine, Paclitaxel, or Pemetrexed)) are recommended for patients with adenocarcinoma and squamous cell NSCLC intolerant to Cisplatin and Pembrolizumab combination therapy regimens and those with comorbidities
    • Combination with albumin-bound Paclitaxel, Docetaxel, Gemcitabine, or Paclitaxel may be used for patients with squamous cell or adenocarcinoma NSCLC patients with PS of 0-1
    • Combination with Pemetrexed is only recommended for adenocarcinoma NSCLC patients with PS of 0-1
    • Albumin-bound Paclitaxel combined with Carboplatin for patients with advanced NSCLC with PS 0-1 is preferred by the NCCN panel over standard Paclitaxel due to its lesser neurotoxicity and better response rate
  • Cisplatin-based combinations (eg Cisplatin plus either Paclitaxel, Docetaxel, Gemcitabine, Vinorelbine,Etoposide, Pemetrexed or albumin-bound Paclitaxel) are recommended for patients with nonsquamous and squamous cell NSCLC
    • Combination with Etoposide, Gemcitabine, Docetaxel, or Paclitaxel may be used for patients with squamous and non-squamous cell NSCLC patients with PS of 0-1
    • Combination with Pemetrexed is only recommended for non-squamous cell NSCLC patients with PS of 0-1
    • Cisplatin + Pemetrexed regimen has been shown more effective and with reduced toxicity as compared with Cisplatin + Gemcitabine regimen; Cisplatin + Gemcitabine has superior efficacy in patients with squamous histology compared to Cisplatin + Pemetrexed
  • Gemcitabine-based combinations (Gemcitabine + Docetaxel or Vinorelbine) are recommended for both PS 0-1 nonsquamous or squamous cell NSCLC with contraindications to Pembrolizumab or Atezolizumab
  • Platinum-based regimens have been shown superior in patients with advanced and non-treatable

Recommended Combination Regimens for Advanced or Metastatic NSCLC or NSCLC NOS with PS 2   

  • Single agent therapy or platinum-based combination regimens are alternative treatment options for patients with PS 2 with advanced/metastatic NSCLC
    • Recommended monotherapies include Gemcitabine, Pemetrexed, or taxanes (eg Docetaxel, albumin-bound and standard Paclitaxel)
      • Pemetrexed monotherapy is only recommended for non-squamous cell NSCLC
    • Carboplatin-based combinations (Carboplatin + albumin-bound Paclitaxel, Docetaxel, Gemcitabine, Paclitaxel, or Pemetrexed) and Gemcitabine-based combinations (Gemcitabine + Docetaxel or Vinorelbine) are alternative therapeutic options for both squamous and nonsquamous cell NSCLC
Patients with Sensitizing EGFR Mutations 
  • Osimertinib or Erlotinib or Afatinib or Gefitinib or Dacomitinib are recommended as 1st-line therapy in sensitizing EGFR mutation positive patients with advanced, recurrent, or metastatic nonsquamous NSCLC adenocarcinoma
    • Osimertinib is the preferred 1st-line therapy option
  • If mutation was discovered during 1st-line chemotherapy, may opt to continue with the present treatment or may interrupt, or may be followed by another regimen of Osimertinib or Erlotinib or Afatinib or Gefitinib or Dacomitinib
ALK Rearrangement-Positive Patients
  • Alectinib is the preferred treatment among the mentioned 1st line therapy options for patients with metastatic NSCLC positive for ALK rearrangement
  • Other 1st-line therapy options for locally advanced or metastatic ALK rearrangement-positive NSCLC include Brigatinib or Ceritinib or Crizotinib 
  • If mutation was discovered during 1st line chemotherapy, may opt to continue with the present treatment or may interrupt, or may be followed by another regimen of Alectinib or Brigatinib or Crizotinib or Ceritinib
  • Studies showed that patients given Crizotinib have very high response rates and significantly improved symptoms like pain, dyspnea or cough, as well as improved survival rates
    • May be used for NSCLC patients with PS 0-4
    • May cause few side effects (eg increase in aminotransferase) or rare life-threatening pneumonitis
    • Also targets ROS1 gene rearrangements and MET amplification
ROS1 Rearrangement-Positive Patients
  • Crizotinib or Entrectinib are preferred1st-line therapy options for ROS1 rearrangement-positive NSCLC 
    • Ceritinib is also used as a 1st-line therapy option
      • Studies showed that ROS1 rearrangement-positive NSCLC patients given Crizotinib produce high response rates (70-80%)
  • If mutation was discovered during 1st-line chemotherapy, may opt to continue with the present treatment or may interrupt, or may be followed by another regimen of Crizotinib or Entrectinib or Ceritinib
BRAF V600E Mutation-Positive Patients
  • Combination treatment with Dabrafenib plus Trametinib is recommended  
  • Monotherapy with Vemurafenib or Dabrafenib, or initial treatments used for adenocarcinoma and squamous cell carcinoma may also be used as 1st-line therapy
  • If mutation was discovered during 1st-line chemotherapy, may opt to continue with the present treatment or may interrupt, followed by Dabrafenib + Trametinib therapy
NTRK Gene Fusion-Positive Patients
  • Larotrectinib or Entrectinib is the preferred 1st-line therapy option for NTRK gene fusion-positive NSCLC
  • If gene fusion was discovered during 1st-line chemotherapy, may opt to continue with the present treatment or may interrupt, or may be followed by another regimen of Larotrectinib or Entrectinib
PD-L1 Expression-Positive Patients
  • Pembrolizumab monotherapy or (Carboplatin or Cisplatin) + Pemetrexed + Pembrolizumab are the preferred therapy options for PD-L1 expression positive (≥50%) and EGFR, ALK, ROS1, BRAF-negative adenocarcinoma, large cell NSCLC NOS patients without contraindications to Pembrolizumab or Atezolizumab therapy
    • Studies showed that PD-L1 expression-positive NSCLC patients given Pembrolizumab produce high response rates with less treatment-related adverse reactions
    • Carboplatin + Paclitaxel + Bevacizumab + Atezolizumab may also be considered
  • (Carboplatin or Cisplatin) + Pemetrexed + Pembrolizumab is the preferred 1st-line therapy for PD-L1 expression positive (≥1-49%) and EGFR, ALK, ROS1, BRAF-negative adenocarcinoma, large cell NSCLC NOS patients without contraindications to Pembrolizumab or Atezolizumab therapy
    • Carboplatin/Paclitaxel/Bevacizumab/Atezolizumab combination therapy and Pembrolizumab monotherapy may also be considered
  • May proceed to maintenance treatment with Pembrolizumab, Pembrolizumab + Pemetrexed, or Atezolizumab and/or Bevacizumab in patients with adenocarcinoma if with stable disease or adequate treatment response
  • Pembrolizumab or Carboplatin + (Paclitaxel or albumin-bound Paclitaxel) + Pembrolizumab are the preferred therapy options for PD-L1 expression positive (≥50%) and EGFR, ALK, ROS1, BRAF-negative squamous cell carcinoma patients without contraindications to Pembrolizumab or Atezolizumab therapy
  • Carboplatin + (Paclitaxel or albumin-bound Paclitaxel) + Pembrolizumab is the preferred therapy for PD-L1 expression positive (≥1-49%) and EGFR, ALK, ROS1, BRAF-negative squamous cell carcinoma patients without contraindications to Pembrolizumab or Atezolizumab therapy
    • Pembrolizumab monotherapy may also be considered in certain circumstances
  • May proceed to maintenance treatment with Pembrolizumab in patients with squamous cell carcinoma if with stable disease or adequate treatment response
  • Immunohistochemistry (IHC) testing for PD-L1 expression may be done prior to initiation of therapy 

Subsequent Therapy

Patients with Adenocarcinoma, Large Cell, NSCLC NOS with Progressive Disease
  • Nivolumab, Pembrolizumab, or Atezolizumab are indicated as preferred therapy for patients with PS 0-2 with disease progression despite 1st-line systemic therapy
    • Nivolumab is also indicated in patients with metastatic NSCLC
  • Docetaxel or Gemcitabine or Pemetrexed, or Ramucirumab + Docetaxel are indicated as 2nd-line or beyond therapy for patients with PS of 0-2
  • Bevacizumab or Pemetrexed or Bevacizumab + Pemetrexed or Pembrolizumab + Pemetrexed or Atezolizumab + Bevacizumab or Gemcitabine are continuation maintenance treatment options for PS 0-2 patients with responsive or stable disease after 4-6 cycles of systemic therapy
  • Nintedanib + Docetaxel may be considered in patients with PS 0-2 and disease progression 9 months after initiation of therapy
Patients with Squamous Cell Carcinoma with Progressive Disease
  • Nivolumab, Pembrolizumab, or Atezolizumab are indicated as preferred therapy for patients with PS 0-2
  • Docetaxel or Gemcitabine or Pemetrexed or Ramucirumab + Docetaxel are indicated as 2nd-line or beyond therapy for patients with PS of 0-2
  • Pembrolizumab or Gemcitabine are treatment options for PS 0-2 patients with responsive or stable disease after 4-6 cycles of chemotherapy
Patients with Sensitizing EGFR mutation with Progressive Disease
  • May initiate Osimertinib therapy (if not previously given) or continue Erlotinib or Afatinib or Gefitinib or Dacomitinib therapy in asymptomatic patients or symptomatic patients with or without brain metastasis positive for T790M mutation
    • May consider Osimertinib in patients with progressive leptomeningeal disease
  • For symptomatic patients with systemic metastasis positive for T790M mutation but lesions are isolated, may opt to continue present therapy, continue Erlotinib or Afatinib or Gefitinib or Dacomitinib therapy, or may initiate Osimertinib treatment if Osimertinib-naive; consider local treatment
  • For symptomatic patients with systemic metastasis positive for T790M mutation but with multiple lesions, initiation of Osimertinib treatment (if Osimertinib-naive) may be considered if patient is T790M mutation positive  
    • If T790M mutation negative, may consider treatment for adenocarcinoma or squamous cell carcinoma
  • Afatinib + Cetuximab is an option for patients who progressed despite treatment with TKI and chemotherapy
  • For patients with disease progression despite Osimertinib therapy, may continue treatment with Osimertinib if asymptomatic or symptomatic only if the lesion is located in the brain or with an isolated systemic lesion; if with multiple lesions, may consider systemic therapy options for adenocarcinoma or squamous cell carcinoma
ALK Rearrangement-Positive Patients with Progressive Disease
  • May continue Crizotinib therapy, or may initiate Alectinib or Brigatinib or Ceritinib therapy, or may consider local therapy in asymptomatic patients with history of Crizotinib treatment
  • For asymptomatic patients previously given Alectinib, Brigatinib or Ceritinib, may consider local therapy or may continue Alectinib or Brigatinib or Ceritinib therapy
  • For symptomatic patients with brain involvement, may consider local therapy for limited lesions, or may initiate Ceritinib or Alectinib or Brigatinib therapy, may consider local therapy if Crizotinib was previously given, or may continue Alectinib or Brigatinib or Ceritinib therapy if previously given
    • If with disease progression despite subsequent treatment, consider initiation of Lorlatinib therapy or 1st line treatments for adenocarcinoma and squamous cell carcinoma
  • For symptomatic patients with systemic involvement, may consider local therapy or may continue Crizotinib therapy of local therapy in patients with isolated lesions previously given Crizotinib or may continue Alectinib or Brigatinib or Ceritinib therapy if previously given
    • If with disease progression despite subsequent treatment, consider initiation of Lorlatinib therapy or 1st-line treatments for adenocarcinoma and squamous cell carcinoma
  • For symptomatic patients with systemic involvement but with multiple lesions, may initiate Ceritinib or Alectinib or Brigatinib therapy if Crizotinib was previously given, or may consider treatment for adenocarcinoma or squamous cell carcinoma
    • May consider treatment with Lorlatinib if still with disease progression despite treatment with Alectinib or Brigatinib or Ceritinib
ROS1 Rearrangement-Positive Patients with Progressive Disease
  • Consider Lorlatinib therapy or 1st line treatments for adenocarcinoma and squamous cell carcinoma if with disease progression despite treatment with Ceritinib, Entrectinib or Crizotinib
BRAF V600E Mutation-Positive Patients with Progressive Disease
  • Consider 1st line treatments for adenocarcinoma, and squamous cell carcinoma if disease progression occurs despite initial treatment with Dabrafenib + Trametinib, Vemurafenib or Dabrafenib monotherapy, or 1st-line treatments for adenocarcinoma and/or squamous cell carcinoma if progression occurs during 1st-line systemic therapy
  • Dabrafenib + Trametinib combination therapy may also be considered if disease progresses despite using 1st-line treatments for adenocarcinoma and/or squamous cell carcinoma
NTRK Gene Fusion-Positive Patients with Disease Progression
  • Consider 1st-line treatments for adenocarcinoma and squamous cell carcinoma if disease progression occurs despite treatment with Larotrectinib or Entrectinib therapy
  • Larotrectinib or Entrectinib therapy may also be considered if disease progresses despite using 1st-line treatments for adenocarcinoma and/or squamous cell carcinoma
PD-L1 Expression-Positive and EGFR, ALK-Negative or Unknown Patients
  • Consider 1st line treatments for adenocarcinoma and squamous cell carcinoma (eg Nivolumab, Pembrolizumab, Atezolizumab, Docetaxel, Gemcitabine, Ramucirumab + Docetaxel) if disease progression occurs 
  • Alternative immunotherapies used to inhibit PD-L1 or the PD-L1 receptor in patients unresponsive or intolerant to Pembrolizumab therapy include Nivolumab and Atezolizumab  

Maintenance Therapy

  • Given after 4-6 cycles of chemotherapy for PS 0-2 patients with tumor response or disease that did not progress

Continuation Maintenance Therapy

  • Utilizes at least 1 of the agents given as 1st-line treatment
  • The following may be considered in patients with adenocarcinoma, large cell, NSCLC NOS or squamous cell NSCLC negative for rearrangements, mutations
    • Monotherapy with Pembrolizumab or Gemcitabine or Pemetrexed or Bevacizumab
    • Combination therapy with Bevacizumab + Pemetrexed or Pembrolizumab + Pemetrexed or Atezolizumab + Bevacizumab

Switch Maintenance Therapy

  • Utilizes other agents not part of the 1st-line regimen
  • Eg Pemetrexed, Docetaxel
    • Pemetrexed used after 1st-line chemotherapy showed advantage in progression-free and overall survival
    • Pemetrexed may be started after 4-6 cycles of 1st-line platinum-doublet chemotherapy in patients with histologies other than squamous cell carcinoma
    • Docetaxel may be started after 4-6 cycles of 1st-line platinum-doublet regimen in patients with squamous cell carcinoma

Consolidation Therapy

  • Durvalumab is recommended by the NCCN as consolidation therapy for patients with PS 0-1 with unresectable stage III NSCLC who were deemed responsive to chemoradiation therapy

Chemotherapeutic Regimens Used with Radiation Therapy

  • Carboplatin/Cisplatin + Pemetrexed, Paclitaxel + Carboplatin, and Cisplatin + Etoposide combination therapy are the preferred regimens for patients with non-squamous cell NSCLC
  • Paclitaxel + Carboplatin and Cisplatin + Etoposide combination therapy are the preferred regimens for patients with squamous cell NSCLC
  • Combined modality chemotherapy and radiation therapy may be used for patients with stage II-III NSCLC with unresectable disease
  • Efficacy rates are better in patients given concurrent chemoradiation therapy compared to those given chemotherapy after radiation therapy

Postoperative Therapy

  • Platinum-based chemotherapy is recommended for patients with PS of 0-1 who underwent complete resection for NSCLC stage II-IIIA

Other Treatments

  • Cabozantinib and Vandetanib are treatment options for NSCLC patients with RET rearrangements
  • Crizotinib may be used for NSCLC patients with high-level MET amplification or MET exon 14 skipping mutation
  • Nivolumab + Ipilimumab combination therapy or Nivolumab monotherapy is recommended for patients with tumor mutational burden

Chemotherapy for Small Cell Lung Cancer (SCLC)

Initial Therapy

  • Single-agent or combination chemotherapy may be used in managing patients with SCLC
  • Eg Cisplatin + Etoposide, Carboplatin + Etoposide, Irinotecan + Cisplatin, Irinotecan + Carboplatin, Carboplatin + Etoposide + Atezolizumab
  • Etoposide + Cisplatin regimen is the most commonly used initial combination chemotherapy in both limited disease (LD) and extensive disease (ED)
    • More effective and less toxic than alkylator + anthracycline-based regimens
    • Simultaneous use with thoracic radiotherapy is the recommended management for patients with LD but causes increased risk of esophagitis and pulmonary toxicity
  • Carboplatin may be substituted to Cisplatin to decrease vomiting, neuropathy and nephropathy
    • Should only be given to patients with LD if Cisplatin is poorly tolerated or contraindicated
  • Maintenance or consolidation chemotherapy used beyond the standard 4-6 cycles produced minimal prolongation of duration of response without improvement in survival and poses greater risk of toxicity

Subsequent Therapy

  • Provides important palliation in patients with SCLC but the effect depends on the time from initial therapy to relapse
    • If the interval is <3 month, effect of regimen is ≤10%, which indicates a refractory SCLC; if >3 months, expected effect is approximately 25%
    • Paclitaxel, Docetaxel, Gemcitabine, Irinotecan, Temozolomide, Topotecan, Etoposide (oral), Etoposide (oral), Nivolumab +/- Ipilimumab, Pembrolizumab, Vinorelbine, Cyclophosphamide + Doxorubicin + Vincristine, and Bendamustine can be considered in patients with PS of 0-2 that has disease that relapsed in ≤6 months
    • In patients that has disease that relapsed for >6 months, the original regimen should be used
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