Non-Small Cell Lung Cancer Treatment Protocols 

Updated: Nov 17, 2016
  • Author: Marvaretta M Stevenson, MD; Chief Editor: Nagla Abdel Karim, MD, PhD  more...
  • Print

Treatment Recommendations, Early or Localized Disease

Stage I or II Disease

Surgery is recommended for patients with stage I or II non–small cell lung cancer NSCLC) and may provide the best possibility for a cure. Surgery (radiation if the patient is not a surgical candidate), with or without adjuvant chemotherapy based on risk factors, for stages IB and II is generally appropriate.

Adjuvant chemotherapy after surgical resection provides an absolute increase in 5-y survival of approximately 5% [1] ; median 5-y overall survival rates range from 45-70%. No benefit has been shown for adjuvant chemotherapy after surgery for stage I disease; the benefit of adding adjuvant chemotherapy increases as disease stage increases. [1]

Stereotactic body radiotherapy (SBRT) may be used in early-stage NSCLC tumors that are smaller than 5 cm without lymph node involvement. This has become a viable and effective option for patients with early-stage NSCLC who are not surgical candidates and in those with significant co-morbidities. Studies show high local control rates (approximately 90%) for these patients. However, the protocols for SBRT have varied among the published studies.

Adjuvant chemotherapy regimens for stage I or II NSCLC

With chemotherapy for stage I or II NSCLC, the goal is to complete four cycles. Acceptable adjuvant chemotherapy regimens include the following:

  • Cisplatin 50 mg/m 2 IV on days 1 and 8 plus  vinorelbine 25 mg/m 2 IV on days 1, 8, 15, and 22 every 28 d [1, 2, 3, 4, 5, 6] or
  • Cisplatin 100 mg/m 2 IV on day 1 plus  vinorelbine 30 mg/m 2 on days 1, 8, 15, and 22 every 28 d [1, 2, 3, 4, 5, 6] or
  • Cisplatin 75-80 mg/m 2 IV on day 1 plus  vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21 d [1, 2, 3, 4, 5, 6] or
  • Cisplatin 100 mg/m 2 IV on day 1 plus  etoposide 100 mg/m 2 IV on days 1-3 every 28 d [1, 2, 3] or
  • Cisplatin 80 mg/m 2 IV on days 1, 22, 43, and 64 plus  vinblastine 4 mg/m 2 IV on days 1, 8, 15, 22, and 29; then  every 2 wk after day 43 until completion of cisplatin every 21 d [1, 2, 3] or
  • Cisplatin 75 mg/m 2 IV on day 1 plus  gemcitabine 1250 mg/m 2 on days 1 and 8 every 21 d [7] or
  • Cisplatin 75 mg/m 2 IV on day 1 plus  docetaxel 75 mg/m 2 IV on day 1 every 21 d [8] or
  • Cisplatin 75 mg/m 2 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 every 21 d (for non-squamous histologies) [7]

Patients with comorbidities or patients not able to tolerate cisplatin may alternatively use the following regimen:

Next:

Chemoradiation Therapy, Locally Advanced Disease

Stage IIIa or IIIb disease

Treatment recommendations include the use of concurrent chemotherapy and radiation, or chemotherapy and radiation can be given sequentially if necessary. Selected patients (predominantly those with stage IIIa) may be surgical candidates; these patients may receive chemotherapy alone or chemotherapy with radiation before surgical resection. Stage IIIa and IIIb disease are typically treated with a combination of chemotherapy and radiation if the patient is not a surgical candidate

Chemotherapy and radiation therapy are preferably given concurrently, but in patients with poor performance status, these therapies may be given sequentially; the decision to treat the patient with concurrent chemoradiation rather than surgery, radiation, or chemotherapy individually should be made by a multidisciplinary tumor board (including a medical oncologist, radiation therapist, and thoracic surgeon). [7, 11, 12]

Concurrent chemotherapy/radiation therapy regimens

Acceptable chemotherapy regimens for use in concurrent chemotherapy/radiation therapy are as follows:

  • Cisplatin 50 mg/m 2 IV on days 1, 8, 29, and 36 plus  etoposide 50 mg/m 2 IV on days 1-5 and days 29-33 [13, 14, 15, 16, 17] or
  • Cisplatin 100 mg/m 2 IV on days 1 and 29 plus  vinblastine 5 mg/m 2/weekly IV for 5 wk [7, 18] or
  • Carboplatin AUC 2 IV weekly for 7 wk plus  paclitaxel 50 mg/m 2 IV weekly for 7 wk; 3 wk later, it can be followed by two cycles of consolidation chemotherapy with carboplatin AUC 6 IV on day 1 plus  paclitaxel 200 mg/m 2 IV on day 1 every 21 wk [19, 20]
  • Carboplatin AUC 5 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 every 21 d for four cycles [21]
  • Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21 d for three cycles [22]

Sequential chemotherapy/radiation therapy regimens

Acceptable chemotherapy regimens for use in sequential chemotherapy/radiation therapy are as follows:

  • Cisplatin 100 mg/m 2 IV on days 1 and 29 plus  vinblastine 5 mg/m 2/weekly IV on days 1, 8, 15, 22, and 29, followed by radiation therapy [7, 18, 23, 24] or
  • Carboplatin AUC 6 IV on day 1 plus  paclitaxel 200 mg/m 2 IV on day 1 every 21 d for two cycles, followed by radiation therapy [7, 19, 20]
Previous
Next:

First-Line Chemotherapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Patients with metastatic disease (stage IV) or recurrent disease after primary therapy (eg, surgery and/or radiation) should be considered for chemotherapy in order to improve quality of life, palliate symptoms, and improve overall survival. [11, 7] The goal is to treat for four to six cycles unless otherwise specified.

Chemotherapy regimens, including platinum-based doublets, are as follows:

  • Cisplatin 75 mg/m 2 IV on day 1 plus  paclitaxel 175 mg/m 2 IV on day 1 every 21 d [25, 26] or
  • Cisplatin 100 mg/m 2 IV on day 1 plus  gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 28 d [26] or
  • Cisplatin 60 mg/m 2 IV on day 1 plus  gemcitabine 1000 mg/m 2 IV on days 1 and 8 every 21 d [27, 28] or
  • Cisplatin 75 mg/m 2 IV on day 1 plus  docetaxel 75 mg/m 2 IV on day 1 every 21 d [8, 26] or
  • Carboplatin AUC 6 IV on day 1 plus  paclitaxel 175-225 mg/m 2 IV on day 1 every 21 d [26, 29] or
  • Carboplatin AUC 6 IV on day 1 plus  paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 every 28 d [30, 31, 32] or
  • Paclitaxel protein bound 100 mg/m2 IV on days 1, 8, and 15 of every 21 d plus carboplatin AUC 6 IV on day 1 [33] or
  • Carboplatin AUC 6 IV on day 1 plus  docetaxel 75 mg/m 2 IV on day 1 every 21 d [17] or
  • Carboplatin AUC 5 IV on day 1 plus  gemcitabine 1250 mg/m 2 IV on days 1 and 8 every 21 d [34, 35, 36] or
  • Cisplatin 100 mg/m 2 IV on day 1 every 28 d plus  vinorelbine 25 mg/m 2 IV weekly [8] or
  • Cisplatin 40 mg/m 2 IV on day 1 plus  vinorelbine 25 mg/m 2 IV on days 1 and 8 every 21 d [27] or
  • Carboplatin AUC 5 IV on day 1 plus  vinorelbine 30 mg/m 2 IV on days 1 and 8 every 21 d [37]

First-line treatment of metastatic squamous NSCLC is as follows:

  • Paclitaxel protein bound 100 mg/m2 IV on days 1, 8, and 15 of every 21 d plus carboplatin AUC 6 IV on day 1 [33] or
  • Necitumumab 800 mg IV infused over 1 h on days 1 and 8 prior to gemcitabine 1250 mg/m 2 IV on days 1 and 8 plus and cisplatin 75 mg/m 2 IV on day 1 of each 21-day cycle [106]

Bevacizumab-based regimens for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis) are as follows:

  • Carboplatin AUC 6 IV on day 1 plus  paclitaxel 200 mg/m 2 IV on day 1 plus  bevacizumab 15 mg/kg IV on day 1 every 21 d (continue bevacizumab every 21 d after four to six cycles are completed; continue until disease progression) [38] or
  • Cisplatin 80 mg/m 2 IV on day 1 plus  gemcitabine 1250 mg/m 2 IV on days 1 and 8 plus  bevacizumab 7.5-15 mg/kg IV on day 1 every 21 d (continue bevacizumab every 21 d after four to six cycles are completed); continue until disease progression or
  • Docetaxel 75 mg/m 2 IV on day 1 plus  bevacizumab 15 mg/kg IV on day 1 every 21 d until disease progression or 52 wk of therapy [12] or
  • Carboplatin AUC 6 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 plus  bevacizumab 15 mg/kg IV on day 1 every 21 d, with pemetrexed and bevacizumab continued until disease progression (plus folate and vitamin B12 supplements, along with dexamethasone premedication for pemetrexed) [39]

Pemetrexed-based regimens for patients who meet eligibility requirements (non-squamous histology) are as follows:

  • Cisplatin 75 mg/m 2 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 every 21 d (plus folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) [40] or
  • Carboplatin AUC 5 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 every 21 d (plus folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) [36, 41, 42]

Treatment recommendations for tumors with epidermal growth factor receptor (EGFR) immunohistochemistry are as follows:

  • Cisplatin 80 mg/m 2 IV on day 1 plus  vinorelbine 25 mg/m 2 IV on days 1 and 8 plus cetuximab 400 mg/m 2 IV loading dose, followed by 250 mg/m 2 IV weekly every 21 d (continue cetuximab weekly after four to six cycles completed, until disease progression) [43, 44]

Erlotinib, afatinib, and gefitinib are approved by the U.S. Food and Drug Administration (FDA) for first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test, [45]  such as the cobas EGFR mutation test [46] and therascreen EGFR RGQ PCR Kit. Treatment recommendations include the following:

Treatment recommendations for anaplastic lymphoma kinase (ALK)–positive locally advanced or metastatic tumors are as follows:

  • Crizotinib 250 mg PO BID until disease progression; dosing interruption and/or dose reduction to 200 mg PO BID may be required, based on safety and tolerability; decrease to 250 mg PO daily if further reduction is needed [57]
  • Crizotinib resistance/intolerance: Ceritinib 750 mg PO daily until disease progression; dosing interruption and/or dose reduction may be required based on safety and tolerability [58]
  • Crizotinib resistance/intolerance: Alectinib 600 mg PO BID until disease progression; dosing interruption and/or dose reduction may be required based on safety and tolerability [108]

Tumors with high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations are as follows: [113]

  • Pembrolizumab 200 mg IV q3wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression

Treatment recommendations for patients with contraindications to carboplatin or cisplatin are as follows:

  • Gemcitabine 1100 mg/m 2 IV on days 1 and 8 plus docetaxel 100 mg/m 2 IV on day 8 every 21 d [59, 60] or
  • Gemcitabine 1000-1200 mg/m 2 IV on days 1 and 8 plus vinorelbine 25-30 mg/m 2 IV on days 1 and 8 every 21 d [37, 61, 62, 63]
Previous
Next:

Second-Line Chemotherapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Second-line chemotherapy is given for advanced or recurrent disease after disease progression following first-line therapy. Second-line regimens are as follows:

  • Nivolumab 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity [71] or
  • Pembrolizumab 200 mg IV every 3 weeks until disease progression or unacceptable toxicity (for up to 24 mo) in tumors that are PD-L1 positive; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab [72] or
  • Docetaxel 75 mg/m 2 IV on day 1 every 21 d (goal, four to six cycles) [64, 65, 66, 67, 68] +/- ramucirumab 10 mg/kg IV [70] or
  • Pemetrexed 500 mg/m 2 IV on day 1 (non-squamous histology) every 21 d (goal, four to six cycles; include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) [68] or
  • Erlotinib 150 mg PO daily for patients with EGFR mutation or gene amplification; given until disease progression [7, 29, 47, 48, 49, 50, 51, 52, 53]
  • Afatinib 40 mg PO daily for patients with metastatic squamous NSCLC that has progressed after platinum-based chemotherapy [110]
  • A study by Herbst et al confirms that bevacizumab and erlotinib should not be used together for refractory or recurrent NSCLC at this time; erlotinib alone in second-line and third-line settings remains the standard of care [69]
Previous
Next:

Third-Line Chemotherapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Third-line chemotherapy is given for advanced or recurrent non–small cell lung cancer (NSCLC) after disease progression following first-line and second-line therapy. Options include erlotinib, ramucirumab, and nivolumab.

Erlotinib is indicated for patients with EGFR mutation or gene amplification. It is given in a dosage of 150 mg PO daily until disease progression. [7, 29, 47, 48, 49, 50, 51, 52, 53]

Ramucirumab is indicated for metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. The regimen is as follows:

  • Ramucirumab 10 mg/kg IV infused over ~1 h prior to docetaxel (75 mg/m 2) IV infusion on day 1 of a 21-d cycle; continue until disease progression or unacceptable toxicity [70]

Nivolumab is indicated for metastatic squamous and nonsquamous (including adenomas) NSCLC with progression on or after platinum-based chemotherapy. [71]

The regimen is as follows:

  • Nivolumab: 3 mg/kg IV every 14 days; continue until disease progression or unacceptable toxicity

Pembrolizumab is indicated for metastatic NSCLC in patients whose tumors express PD-L1 who also have disease progression on or after platinum-containing chemotherapy. [72]

The regimen is as follows:

  • Pembrolizumab 200 mg IV every 3 weeks; continue until disease progression or unacceptable toxicity (for up to 24 mo) 
Previous
Next:

Single-Agent Therapy, Metastatic or Recurrent Disease

Stage IV or Recurrent Disease

Single-agent therapy is a reasonable first-line option in patients with good performance status (ECOG score ≤2) disease or in the elderly; the goal is to complete four to six cycles. Systemic chemotherapy is not indicated for patients with poor performance status (ECOG 3-4), except for erlotinib in patients who are EGFR-mutation positive. [7]

Single-agent regimens include the following:

  • Paclitaxel 200 mg/m 2 IV every 21 d [73, 74] or
  • Docetaxel 35 mg/m 2 IV weekly for 3 wk every 4wk [60, 64, 67, 75] or
  • Docetaxel 75 mg/m 2 IV every 21 d [64, 65, 66, 67] or
  • Gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 4 wk [76, 77] or
  • Gemcitabine 1250 mg/m 2 IV on days 1 and 8 every 21 d [34, 61] or
  • Vinorelbine 25 mg/m 2 IV weekly [78, 79] or
  • Vinorelbine 30 mg/m 2 IV on days 1 and 8 every 21d [61, 80, 81] or
  • Pemetrexed 500 mg/m 2 IV every 21d [68] (non-squamous histology)

EGFR T790M mutation positive NSCLC detected by an FDA approved test, in patients who have progressed on or after EGFR TKI therapy

  • Osimertinib 80 mg PO once daily until disease progression or unacceptable toxicity [107]

ROS-1 mutation positive NSCLC

  • Crizotinib 250 mg PO q12h until disease progression or unacceptable toxicity [109]

Disease progression during or following platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab

  • Atezolizumab 1200 mg IV q3wk until disease progression or unacceptable toxicity [111, 112]
Previous
Next:

Maintenance Chemotherapy, Metastatic or Recurrent Disease

Stage IV Disease

Maintenance chemotherapy may be considered for patients with advanced (stage IV) disease who have a disease response or stable disease after completing first-line chemotherapy

Switch Maintenance Chemotherapy

Switch maintenance chemotherapy involves giving chemotherapy with agents different from those used in first-line therapy. This chemotherapy is given after completing first-line chemotherapy until disease progression or unacceptable toxicities occur. Switch maintenance therapy is associated with improvements in progression-free survival for all three agents listed below and improvements in overall survival for pemetrexed and erlotinib.

Switch maintenance chemotherapy regimens are as follows:

  • Docetaxel 75 mg/m 2 IV every 21 d [82] or
  • Pemetrexed 500 mg/m 2 IV every 21 d [83] (non-squamous histology) or
  • Erlotinib 150 mg PO daily (1 h before or 2 h after meals) [84]

Continuation Maintenance Therapy

Continuation maintenance therapy involves giving chemotherapy that was part of the first-line therapy, after completion of four to six cycles of first-line therapy. This chemotherapy is given until disease progression or unacceptable toxicities occur. The following regimens have been associated with improvements in progression-free survival and overall survival:

  • Cisplatin 80 mg/m 2 IV on day 1 plus  vinorelbine 25 mg/m 2 IV on days 1 and 8 plus  cetuximab 400 mg/m 2 IV loading dose, followed by 250 mg/m 2 IV weekly every 21 d; continue cetuximab weekly after four to six cycles completed, until disease progression [43, 44] (for tumors with EGFR-positive immunohistochemistry)
  • Carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m 2 IV on day 1 plus  bevacizumab 15 mg/kg IV on day 1 every 21 d; continue bevacizumab every 21 d after four to six cycles completed, until disease progression for patients who meet eligibility requirements (non-squamous histology, treated brain metastases, no history of hemoptysis) [38]
  • Carboplatin AUC 6 IV on day 1 plus  pemetrexed 500 mg/m 2 IV on day 1 plus  bevacizumab 15 mg/kg IV on day 1 every 21 d; after four cycles have been completed, pemetrexed and bevacizumab are continued until disease progression (include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) [39]
  • Cisplatin 75 mg/m 2 IV on day 1 plus pemetrexed 500 mg/m 2 IV on day 1 every 21 d; after four cycles have been completed, pemetrexed is continued until disease progression (include folate and vitamin B12 supplements along with dexamethasone premedication for pemetrexed) [85]
Previous
Next:

Special Considerations

Preoperative Staging and Imaging

Patients with certain situations who being considered for curative surgical resection should undergo invasive mediastinal staging and extrathoracic imaging (head computed tomography (CT) or magnetic resonance imaging (MRI) with either whole-body positron-emission tomography (PET) or abdominal CT plus bone scan. Involvement of mediastinal nodes and/or metastatic disease represents a contraindication to resection. These situations are as follows [11, 7] :

  • Pancoast tumor (superior sulcus tumor)
  • Clinical T4N0/1M0 tumors
  • Two synchronous primary NSCLCs
  • A metachronous NSCLC
  • Stage I or II primary lung cancer with an isolated brain metastasis
  • Isolated adrenal metastasis
  • NSCLC tumor invading the chest wall

Histology

Histology must be determined by pathologic review for NSCLC. Histologic findings may influence therapeutic choices, as follows:

  • Pemetrexed is indicated for non-squamous tumors only [11, 7]
  • Bevacizumab is contraindicated for squamous tumors due to the risk of pulmonary hemorrhage
  • Erlotinib has higher response rates for adenocarcinomas with EGFR mutations
  • Erlotinib should be considered for patients with EGFR mutations (activating mutations in exons 19 or 21); patients with the highest response rates typically are Asian, female, have never smoked or are light smokers, and have adenocarcinomas; response rates in unselected populations can be 10-20% or lower but increase to up to 90% in selected populations [7, 29, 47, 48, 49, 50, 51, 52, 53]
Previous