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, & 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, & in patients w/ metastatic disease
  • 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

Recommended Combination Regimens for Advanced or Metastatic NSCLC or NSCLC NOS with PS 0-1, Negative for ALK or ROS1 Rearrangements, EGRF Mutations, or PD-L1 Expression       
  • Pembrolizumab-based regimens
    • Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin combination is the preferred regimen for patients with non-squamous cell NSCLC 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 nonsquamous cell NSCLC patients with PS of 0-1
  • Bevacizumab-based regimens (Bevacizumab + Pemetrexed + Carboplatin or Cisplatin, Bevacizumab + Carboplatin + Paclitaxel) are only recommended for patients with nonsquamous cell NSCLC
    • Criteria for receiving Bevacizumab + chemotherapy: Nonsquamous NSCLC & absence of hemoptysis
    • Bevacizumab should be given until disease progression but should be used cautiously in patients with risk of thrombocytopenia & bleeding
  • Carboplatin-based combinations (Carboplatin plus either albumin-bound Paclitaxel, Docetaxel, Etoposide, Gemcitabine, Paclitaxel, or Pemetrexed)) are recommended for patients with nonsquamous & squamous cell NSCLC intolerant to Cisplatin & Pembrolizumab combination therapy regimens & those with comorbidities
    • Combination with albumin-bound Paclitaxel, Docetaxel, Gemcitabine, or Paclitaxel may be used for patients with squamous & nonsquamous cell NSCLC patients with PS of 0-1
    • Combination with Pemetrexed is only recommended for nonsquamous cell NSCLC patients with PS of 0-1
    • Combination with Etoposide is only recommended for squamous cell NSCLC patients with PS 2
    • 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 & 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 & squamous cell NSCLC
    • Combination with Etoposide, Gemcitabine, Docetaxel, or Paclitaxel may be used for patients with squamous & 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 & 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 & non-treatable

Recommended Combination Regimens for Advanced or Metastatic NSCLC or NSCLC NOS with PS 2, Negative for ALK or ROS1 Rearrangements, EGRF Mutations, or PD-L1 Expression       

  • Single agent therapy or platinum-based regimens are alternative treatment options for patients w/ PS 2 w/ advanced/metastatic NSCLC
    • Recommended monotherapies include Gemcitabine, Pemetrexed, or taxanes (eg Docetaxel, albumin-bound & standard Paclitaxel)
      • Pemetrexed monotherapy is only recommended for non-squamous cell NSCLC
    • Carboplatin-based combinations (Carboplatin + albumin-bound Paclitaxel, Docetaxel, Etoposide, Gemcitabine, Paclitaxel, or Pemetrexed) & Gemcitabine-based combinations (Gemcitabine + Docetaxel or Vinorelbine) are alternative therapeutic options for both squamous & nonsquamous cell NSCLC
Patients with Sensitizing EGFR Mutations 
  • Erlotinib or Gefitinib or Afatinib or Osimertinib or Dacomitinib 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
    • 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 Erlotinib or Afatinib or Gefitinib or Osimertinib or Dacomitinib
ALK Rearrangement-Positive Patients
  • Alectinib or Brigatinib 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 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 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 or Ceritinib are recommended 1st-line therapy options for ROS1 rearrangement-positive NSCLC 
  • 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%)
  • If mutation was discovered during 1st-line chemotherapy, may opt to continue w/ the present treatment or may interrupt, or may be followed by another regimen of Crizotinib or Ceritinib
BRAF V600E Mutation-Positive Patients
  • Combination treatment with Dabrafenib plus Trametinib is recommended  
  • May consider 1st line treatments used for adenocarcinoma, & squamous cell carcinoma
  • If mutation was discovered during 1st-line chemotherapy, may opt to continue with the present treatment or may interrupt, followed by Dabrafenib + Trametinib therapy
  • Single-agent Vemurafenib or Dabrafenib monotherapy may be considered if combination therapy with Dabrafenib plus Trametinib is not tolerated by patient 
PD-L1 Expression-Positive & EGFR, ALK-Negative or Unknown Patients
  • Pembrolizumab is the gold standard 1st-line therapy for PD-L1 expression positive (≥50%) & EGFR, ALK-negative or unknown non-small cell lung cancer (NSCLC) & those without contraindications to treatment with Pembrolizumab or Atezolizumab 
    • Studies showed that PD-L1 expression-positive NSCLC patients given Pembrolizumab produce high response rates with less treatment-related adverse reactions
  • May consider (Carboplatin or Cisplatin) + Pemetrexed + Pembrolizumab or Carboplatin + Paclitaxel +Bevacizumab + Atezolizumab for patients with adenocarcinoma, large cell, NSCLC NOS
    • May proceed to maintenance treatment with Pembrolizumab, Pembrolizumab + Pemetrexed, or Atezolizumab &/or Bevacizumab if with stable disease or adequate treatment response
  • May consider treatment with adenocarcinoma therapeutic regimens if with disease progression
  • (Carboplatin or Cisplatin) + (Paclitaxel or Albumin-bound Paclitaxel) + Pembrolizumab for patients with squamous cell carcinoma
    • May proceed to maintenance treatment with Pembrolizumab if with stable disease or adequate treatment response
    • May consider treatment with squamous cell carcinoma therapeutic regimens if with disease progression 
  • 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 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 &/or Bevacizumab or Gemcitabine are treatment options for PS 0-2 patients with responsive or stable disease after 4-6 cycles of systemic 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 w/ 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 pulse Erlotinib in patients with carcinomatosis meningitis
  • 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, 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 Crizotinib therapy, or may initiate Alectinib or Brigatinib or Ceritinib therapy in asymptomatic patients w/ history of Crizotinib treatment
  • For symptomatic patients with brain involvement, may consider local therapy for limited lesions & 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 subsequent treatment, consider initiation of Lorlatinib therapy or 1st line treatments for adenocarcinoma & 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
    • If with disease progression despite subsequent treatment, consider initiation of Lorlatinib therapy or 1st-line treatments for adenocarcinoma & 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 & squamous cell carcinoma if with disease progression despite treatment with Ceritinib or Crizotinib
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 & EGFR, ALK-Negative or Unknown Patients
  • 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 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
  • Patients with nonsquamous NSCLC & negative for rearrangements, mutations, & with PD-L1 expression <50% or unknown
    • Bevacizumab may be continued after 4-6 cycles of platinum-doublet + Bevacizumab chemotherapy
    • Pemetrexed monotherapy
    • Bevacizumab + Pemetrexed if Pemetrexed/platinum-based combination chemotherapy regimen was used as 1st-line therapy
    • Pembrolizumab + Pemetrexed if Pembrolizumab/Carboplatin or Cisplatin/Pemetrexed combination therapy was used initially
    • Atezolizumab &/or Bevacizumab if Atezolizumab/Carboplatin/Paclitaxel/Bevacizumab combination therapy was given
    • Gemcitabine may be continued after 4-6 cycles of platinum-doublet chemotherapy
  • Pembrolizumab monotherapy, Pembrolizumab + Pemetrexed or Atezolizumab &/or Bevacizumab combination therapies are options for patients with adenocarcinoma, large cell, NSCLC NOS positive for PD-L1 expression
  • Pembrolizumab monotherapy is the recommended continuation maintenance treatment for patients with squamous cell carcinoma positive for PD-L1 expression
  • Gemcitabine monotherapy may also be considered for both squamous & nonsquamous NSCLC negative for ALK or ROS1 rearrangements, sensitizing EGFR mutations, BRAF V600E mutations, or PD-L1 expression

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

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

  • Eg Cisplatin + Etoposide, Cisplatin + Vinblastine, Carboplatin + Paclitaxel
  • Carboplatin/Cisplatin + Pemetrexed may be used for patients with nonsquamous cell NSCLC
  • Combined modality chemotherapy & radiation therapy may be used for patients with stage IIIA-B 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 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, 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 & 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, Pembrolizumab, 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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