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

Chemotherapy/Targeted Therapy for Non-Small Cell Lung Cancer (NSCLC)
  • Recommended in patients with advanced 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, & 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 non-small cell lung cancer (NSCLC)
    • Histologic subtype & genetic alterations 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
  • Platinum-based chemotherapy lengthens survival, improves symptom control & offers better quality of life
    • No specific platinum-based regimen is superior to the other

First-line Therapy

  • Two drug regimen is preferred in patients with Performance Status (PS) of 0-1 treatment-naive non-small cell lung cancer (NSCLC)
    • Addition of 3rd cytotoxic drug did not show increase in survival rate, except for Bevacizumab
    • Cisplatin-based regimens have been shown superior in patients with advanced & non-treatable disease, with 6-12 weeks improvement in median survival & 10-15% improvement in 1 year survival rates
    • Cisplatin or Carboplatin has been shown effective in combination with either Paclitaxel, Docetaxel, Gemcitabine, Vinorelbine, Etoposide, Vinblastine, Pemetrexed or albumin-bound Paclitaxel
      • Albumin-bound Paclitaxel combined with Carboplatin for patients with advanced non-small cell lung cancer (NSCLC) with PS 0-1 is preferred by the NCCN panel over standard Paclitaxel due to its lesser neurotoxicity & better response rate
      • Cetuximab + Vinorelbine/Cisplatin may be an option for patients with PS 0-1 
    • Recommended 1st-line regimens for non-squamous cell non-small cell lung cancer (NSCLC) include Cisplatin or Carboplatin + Pemetrexed, Carboplatin + Paclitaxel with or without Bevacizumab, & Gemcitabine + Cisplatin
      • Cisplatin + Pemetrexed regimen has been shown more effective and with reduced toxicity as compared with Cisplatin + Gemcitabine regimen; also has superior efficacy in patients with squamous histology compared to Cisplatin + Pemetrexed
    • Bevacizumab combination therapy is recommended in patients with advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC) or non-small cell lung cancer (NSCLC) NOS with PS 0-1 negative for ALK or ROS1 rearrangements, EGFR mutations, or PD-L1 expression
      • Criteria for receiving Bevacizumab + chemotherapy: nonsquamous non-small cell lung cancer (NSCLC) & absence of hemoptysis
      • Bevacizumab should be given until disease progression but should be used cautiously in patients with risk of thrombocytopenia & bleeding
  • The 3-drug regimen Pembrolizumab-Carboplatin-Pemetrexed is now recommended by the NCCN panel for patients with advanced non-squamous non-small cell lung cancer (NSCLC) or non-small cell lung cancer (NSCLC) NOS
  • Single agent therapy or reduced-dose platinum-based regimen are alternative treatment options for patients with PS 2 with advanced non-small cell lung cancer (NSCLC) adenocarcinoma
Patients with Sensitizing EGFR Mutations 
  • Erlotinib or Gefitinib or Afatinib (in select patients) are recommended as 1st-line therapy in sensitizing epidermal growth factor receptor (EGFR) mutation positive patients with advanced, recurrent, or metastatic nonsquamous non-small cell lung cancer (NSCLC) adenocarcinoma
  • 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 Erlotinib or Afatinib or Gefitinib
ALK Rearrangement-Positive Patients
  • Alectinib or Crizotinib or Ceritinib are recommended 1st-line therapy options for locally advanced or metastatic ALK rearrangement-positive non-small cell lung cancer (NSCLC) with PS 0-4 
    • Alectinib is the preferred treatment among the mentioned 1st line therapy option for patients with metastatic non-small cell lung cancer (NSCLC) positive for ALK rearrangement
  • 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 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 non-small cell lung cancer (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 is the gold standard for 1st-line therapy
    • Studies showed that ROS1 rearrangement-positive non-small cell lung cancer (NSCLC) patients given Crizotinib produce high response rates (≥70%)
BRAF V600E Mutation-Positive Patients
  • Combination treatment with Dabratenib plus Trametinib is recommended  
  • May consider 1st line treatments used for adenocarcinoma, & squamous cell carcinoma
  • Vemurafenib or Dabrafenib monotherapy may be considered if combination therapy Dabratenib plus Trametinib  is not tolerated by patient 
PD-L1 Expression-Positive Patients
  • Pembrolizumab is the gold standard 1st-line therapy for PD-L1 expression positive & EGFR, ALK, ROS1 or BRAF-negative non-small cell lung cancer (NSCLC) 
  • Studies showed that PD-L1 expression-positive NSCLC patients given Pembrolizumab produce high response rates with less treatment-related adverse reactions
  • Immunohistochemistry (IHC) testing for PD-L1 expression may be done prior to initiation of therapy 

Subsequent Therapy

Patients with Adenocarcinoma or Large Cell Carcinoma with Progressive Disease
  • Nivolumab, Pembrolizumab, or Atezolizumab are indicated as preferred therapy for patients with PS 0-2 with disease progression despite 1st-line chemotherapy
    • Nivolumab is also indicated in patients with metastatic NSCLC
  • Docetaxel, Gemcitabine, Pemetrexed, or Ramucirumab + Docetaxel & other systemic therapy is indicated as 2nd-line or beyond therapy for patients with PS of 0-2
  • Bevacizumab or Pemetrexed or Bevacizumab + Pemetrexed or Gemcitabine are treatment options for PS 0-2 patients with responsive or stable disease after 6-4 cycles of chemotherapy
Patients with Squamous Cell Carcinoma with Progressive Disease
  • Nivolumab, Pembrolizumab, or Atezolizumab are indicated as preferred therapy for patients with PS 0-2
  • Docetaxel, Gemcitabine, or Ramucirumab + Docetaxel & other systemic therapy are indicated as 2nd-line therapy for patients with PS of 0-2
Patients with Sensitizing EGFR mutation with Progressive Disease
  • May initiate Osimertinib therapy or continue Erlotinib or Afatinib or Gefitinib therapy in asymptomatic patients or symptomatic patients with brain metastasis positive for T790 mutation
    • May consider pulse Erlotinib in patients with carcinomatosis meningitis
  • For symptomatic patients with systemic metastasis positive for T790 mutation but lesions are isolated, may opt to continue present therapy, continue Erlotinib or Afatinib or Gefitinib therapy, or may initiate Osimertinib treatment if Osimertinib-naive 
  • For symptomatic patients with systemic metastasis positive for T790 mutation but with multiple lesions, initiation of Osimertinib treatment (if Osimertinib-naive) may be considered if patient is T790 mutation positive  
    • If T790 mutation negative, may consider treatment for adenocarcinoma, squamous cell carcinoma, or patient may be PD-L1 expression positive
  • Afatinib + Cetuximab is an option for patients who progressed despite treatment with TKI and chemotherapy
ALK Rearrangement-Positive Patients with Progressive Disease
  • May continue Alectinib or Crizotinib or Ceritinib therapy, or may initiate Ceritinib or Alectinib or Brigatinib therapy in asymptomatic patients
  • For symptomatic patients with brain involvement, may consider local therapy & continue treatment with Alectinib or Crizotinib or Ceritinib, or may initiate Ceritinib or Alectinib or Brigatinib therapy if not previously given
    • If with disease progression despite previous treatment, consider 1st line treatments for adenocarcinoma, squamous cell carcinoma, PD-L1 expression positive NSCLC
  • For symptomatic patients with systemic involvement, may consider local therapy or may continue Alectinib or Crizotinib or Ceritinib therapy in patients with isolated lesions
  • For symptomatic patients with systemic involvement but with multiple lesions, may initiate Ceritinib or Alectinib or Brigatinib therapy, or may consider treatment for adenocarcinoma or squamous cell carcinoma
  • Crizotinib, Alectinib, or Brigatinib may be given to patients with metastatic NSCLC positive for ALK rearrangement who are intolerant or unresponsive to Crizotinib therapy
ROS1 Rearrangement-Positive Patients with Progressive Disease
  • Consider 1st line treatments for adenocarcinoma, squamous cell carcinoma, PD-L1 expression positive NSCLC
BRAF V600E Mutation-Positive Patients with Progressive Disease
  • Consider 1st line treatments for adenocarcinoma, & squamous cell carcinoma if  disease progression occurs
  • Dabrafenib + Trametinib combination therapy may also be considered if disease progresses despite using 1st-line treatments for adenocarcinoma &/or squamous cell carcinoma
  • Single agent therapy with Dabrafenib or Vemurafenib are treatment options for BRAF V600E mutation-positive patients who are intolerant of combination regimens
PD-L1 Expression-Positive Patients with Progressive Disease
  • Consider 1st line treatments for adenocarcinoma, & 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 & Atezolizumab  

Maintenance Therapy

  • Given after 4-6 cycles of chemotherapy for 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
  • Eg Bevacizumab, Cetuximab, Gemcitabine, Pemetrexed
    • Bevacizumab may be continued after 4-6 cycles of platinum-doublet chemotherapy + Bevacizumab
    • Cetuximab may be continued after 4-6 cycles of Cisplatin, Vinorelbine, & Cetuximab
    • Pemetrexed may be continued after 4-6 cycles of Cisplatin + Pemetrexed chemotherapy in patients with histologies other than squamous cell carcinoma
    • Gemcitabine may be continued after 4-6 cycles of platinum-doublet chemotherapy

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 & 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

Postoperative Therapy

  • Platinum-based chemotherapy is recommended for patients with PS of 0-1 who underwent complete resection for non-small cell lung cancer (NSCLC) stage II-IIIA

Other Treatments

  • Cabozantinib & 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

Chemotherapy for Small-Cell Lung Cancer (SCLC)

Initial therapy

  • Single-agent or combination chemotherapy may be used in managing patients with small cell lung cancer (SCLC)
  • Eg Cisplatin + Etoposide, Carboplatin + Etoposide, Irinotecan + Cisplatin, Irinotecan + Carboplatin
  • Etoposide + Cisplatin regimen is the most commonly used initial combination chemotherapy in both limited disease (LD) and extensive disease (ED)
    • More effective & less toxic than alkylator + anthracycline-based regimens
    • Simultaneous use with thoracic radiotherapy is the recommended management for patients with limited disease (LD) but causes increased risk of esophagitis & pulmonary toxicity
  • Carboplatin may be substituted to Cisplatin to decrease vomiting, neuropathy & nephropathy
    • Should only be given to patients with limited disease (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 & poses greater risk of toxicity

Subsequent Therapy

  • Provides important palliation in patients with small cell lung cancer (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 small cell lung cancer (SCLC); if >3 months, expected effect is approximately 25%
    • Paclitaxel, Docetaxel, Gemcitabine, Irinotecan, Temozolomide, Topotecan, Etoposide (oral), Etoposide (oral), Nivolumab +/- Ipilimumab, Vinorelbine, Cyclophosphamide + Doxorubicin + Vincristine, & 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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