lunes, 8 de abril de 2019

Non-Small Cell Lung Cancer Treatment (PDQ®) 2/4 —Health Professional Version - National Cancer Institute

Non-Small Cell Lung Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute

Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version



Treatment Option Overview for NSCLC

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.
Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, although overall survival is poor.[3,4]
Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[5,6] however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.
The identification of gene mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[7] In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 and other genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. The MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.
The standard treatment options for each stage of NSCLC are presented in Table 7.
Table 7. Standard Treatment Options for NSCLC
Stage (TNM Staging Criteria)Standard Treatment Options
ALK = anaplastic lymphoma kinase; BRAF = v-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; MEK = MAPK kinase 1; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitors; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body.
Occult NSCLCSurgery
Stage 0 NSCLCSurgery
Endobronchial therapies
Stages IA and IB NSCLCSurgery
Radiation therapy
Stages IIA and IIB NSCLCSurgery
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Radiation therapy
Stage IIIA NSCLCResected or resectable diseaseSurgery
Neoadjuvant therapy
Adjuvant therapy
Unresectable diseaseRadiation therapy
Chemoradiation therapy
Superior sulcus tumorsRadiation therapy alone
Surgery
Chemoradiation therapy followed by surgery
Tumors that invade the chest wallSurgery
Surgery and radiation therapy
Radiation therapy alone
Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLCSequential or concurrent chemotherapy and radiation therapy
Radiation therapy dose escalation for concurrent chemoradiation
Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLCCytotoxic combination chemotherapy
Combination chemotherapy with monoclonal antibodies
Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
EGFR tyrosine kinase inhibitors (for patients with EGFR mutations)
ALK inhibitors (for patients with ALKtranslocations)
ROS1 inhibitors (for patients with ROS1rearrangements)
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations
Immune checkpoint inhibitor for PD-L1 expressing NSCLC.
Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLCChemotherapy
EGFR-directed therapy
ALK-directed TKI
ROS1-directed therapy
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
Immunotherapy
In addition to the standard treatment options presented in Table 7, treatment options under clinical evaluation include the following:
  • Combining local treatment (surgery).
  • Regional treatment (radiation therapy).
  • Systemic treatments (chemotherapy, immunotherapy, and targeted agents).
  • Developing more effective systemic therapy.

Follow-Up

Several small series have reported that reduction in fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.[8-15] Studies have used different timing of assessments, 18F-FDG PET parameters, and cutpoints to define 18F-FDG PET response. Reduction in maximum standardized uptake value (SUV) of higher than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[16] Median survival after resection was longer for patients with tumor SUV values of lower than 4 (56 months vs. 19 months).[15] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[17]
18F-FDG PET may be more sensitive and specific than computed tomography (CT) scan in assessing response to induction therapy. Optimal timing of imaging remains to be defined; however, one study suggested that greater sensitivity and specificity of 18F-FDG PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[16]
There is no clear role for routine posttreatment PET-CT scans.[18][Level of evidence: 3iiA]
Evidence (surveillance imaging after radiation therapy with or without chemotherapy):
  1. A prospective multicenter trial led by the American College of Radiology Imaging Network (ACRIN) and the Radiation Therapy Oncology Group (RTOG) cooperative group (ACRIN 6668/RTOG 0235 [NCT00083083]) studied the role of posttreatment PET-CT at approximately 14 weeks (range, 12–16 weeks) to predict overall survival (OS) after standard-of-care concurrent chemotherapy and radiation therapy in 173 patients with stage III disease.
    • The primary endpoint was to determine the relationship between SUVpeak at a prespecified binary cutoff of SUVpeak 3.5 with OS.
    • The study demonstrated no association between OS and SUVpeak of 3.5 or lower compared with SUVpeak higher than 3.5 with 2-year OS estimates of 51% vs. 37% (P = 0.29).
    • Exploratory analyses showed associations between OS and SUVpeak as a continuous variable, and binary cutoffs of SUVpeak 5.0 and 7.0.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Lester JF, MacBeth FR, Coles B: Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 63 (3): 690-4, 2005. [PUBMED Abstract]
  2. Pöttgen C, Eberhardt W, Grannass A, et al.: Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25 (31): 4987-92, 2007. [PUBMED Abstract]
  3. Chemotherapy for non-small cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev (2): CD002139, 2000. [PUBMED Abstract]
  4. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
  5. Spiro SG, Rudd RM, Souhami RL, et al.: Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 59 (10): 828-36, 2004. [PUBMED Abstract]
  6. Clegg A, Scott DA, Hewitson P, et al.: Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 57 (1): 20-8, 2002. [PUBMED Abstract]
  7. Pao W, Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol 12 (2): 175-80, 2011. [PUBMED Abstract]
  8. Curran WJ Jr, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011. [PUBMED Abstract]
  9. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005. [PUBMED Abstract]
  10. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004. [PUBMED Abstract]
  11. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004. [PUBMED Abstract]
  12. Cerfolio RJ, Bryant AS, Winokur TS, et al.: Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg 78 (6): 1903-9; discussion 1909, 2004. [PUBMED Abstract]
  13. Pöttgen C, Levegrün S, Theegarten D, et al.: Value of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction of pathologic response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 12 (1): 97-106, 2006. [PUBMED Abstract]
  14. Eschmann SM, Friedel G, Paulsen F, et al.: 18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34 (4): 463-71, 2007. [PUBMED Abstract]
  15. Hellwig D, Graeter TP, Ukena D, et al.: Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma. J Thorac Cardiovasc Surg 128 (6): 892-9, 2004. [PUBMED Abstract]
  16. Cerfolio RJ, Bryant AS: When is it best to repeat a 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan on patients with non-small cell lung cancer who have received neoadjuvant chemoradiotherapy? Ann Thorac Surg 84 (4): 1092-7, 2007. [PUBMED Abstract]
  17. Mac Manus MP, Hicks RJ, Matthews JP, et al.: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 21 (7): 1285-92, 2003. [PUBMED Abstract]
  18. Machtay M, Duan F, Siegel BA, et al.: Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 31 (30): 3823-30, 2013. [PUBMED Abstract]

Occult NSCLC Treatment

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.
After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar-stage disease.

Standard Treatment Options for Occult NSCLC

Standard treatment options for occult NSCLC include the following:
  1. Surgery.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Stage 0 NSCLC Treatment

Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.[1-3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Standard Treatment Options for Stage 0 NSCLC

Standard treatment options for stage 0 NSCLC include the following:
  1. Surgery.
  2. Endobronchial therapies, including photodynamic therapy, electrocautery, cryotherapy, and neodymium-doped yttrium aluminium garnet (Nd-YAG) laser therapy.

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue because patients with stage 0 NSCLC are at a high risk for second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Endobronchial therapies

Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.[3-6]
Evidence (endobronchial therapies):
  1. Small case series have reported high complete response rates and long-term survival in selected patients.[7,8][Level of evidence: 3iiiDiii]
Efficacy of these treatment modalities in the management of patients with early NSCLC remains to be proven in definitive randomized controlled trials.
There is a high incidence of second primary cancers developing.[1,2]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Woolner LB, Fontana RS, Cortese DA, et al.: Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 59 (7): 453-66, 1984. [PUBMED Abstract]
  2. Venmans BJ, van Boxem TJ, Smit EF, et al.: Outcome of bronchial carcinoma in situ. Chest 117 (6): 1572-6, 2000. [PUBMED Abstract]
  3. Jeremy George P, Banerjee AK, Read CA, et al.: Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax 62 (1): 43-50, 2007. [PUBMED Abstract]
  4. Kennedy TC, McWilliams A, Edell E, et al.: Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 221S-233S, 2007. [PUBMED Abstract]
  5. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
  6. Deygas N, Froudarakis M, Ozenne G, et al.: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120 (1): 26-31, 2001. [PUBMED Abstract]
  7. van Boxem TJ, Venmans BJ, Schramel FM, et al.: Radiographically occult lung cancer treated with fibreoptic bronchoscopic electrocautery: a pilot study of a simple and inexpensive technique. Eur Respir J 11 (1): 169-72, 1998. [PUBMED Abstract]
  8. van Boxem AJ, Westerga J, Venmans BJ, et al.: Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose? Lung Cancer 31 (1): 31-6, 2001. [PUBMED Abstract]

Stages IA and IB NSCLC Treatment

Standard Treatment Options for Stages IA and IB NSCLC

Standard treatment options for stages IA non-small cell lung cancer (NSCLC) and IB NSCLCinclude the following:
  1. Surgery.
  2. Radiation therapy (for patients who cannot have surgery or choose not to have surgery).
Chemotherapy and radiation therapy have not been shown to improve outcomes in stage I NSCLC that has been completely resected.

Surgery

Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.[1]
Evidence (surgery):
  1. The Lung Cancer Study Group conducted a randomized study (LCSG-821) that compared lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed the following:[2]
    • A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.
    • No significant difference in overall survival (OS).
  2. Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3]
    • A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm.
    • The rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.
  3. A study of stage I patients showed the following:[4]
    • Those treated with wedge or segmental resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4]
  4. The Cochrane Collaboration reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[5] A pooled analysis of three trials reported the following:
    • Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and complete ipsilateral mediastinal lymph node dissection (CMLND), compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93, P = .005).[5][Level of evidence: 1iiA]
    • There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).
    • There was no difference in operative mortality.
    • Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).
  5. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030 [NCT00003831]).[6,7]
    • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[6,7]
    • There was no difference in OS, disease-free survival, local recurrence, and regional recurrence.[7][Level of evidence: 1iiA]
Current evidence suggests that lung cancer resection combined with CMLND is not associated with improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal lymph nodes in patients with stage I, II, or IIIA NSCLC.[7][Level of evidence: 1iiA]
Limitations of evidence (surgery):
Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

Adjuvant therapy

Many patients treated surgically subsequently develop regional or distant metastases.[8] Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve the outcome of patients with stage I NSCLC that has been completely resected.
Adjuvant radiation therapy
The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.[9]
Evidence (adjuvant radiation therapy):
  1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[9]
    • An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2–9), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0-N1 disease, whereas for patients with stage III, N2 disease, there was no clear evidence of an adverse effect.
    • Results for local (HR, 1.13; P = .02), distant (HR, 1.14; P = .02), and overall (HR, 1.10; P = .06) recurrence-free survival similarly showed a detriment of PORT.[9][Level of evidence: 1iiA]
Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.
Adjuvant brachytherapy
The value of intraoperative (adjuvant) brachytherapy applied to the suture line has been evaluated in patients undergoing sublobar resections for stage I NSCLC to improve local control; it has not been found to improve outcomes.
Evidence (adjuvant brachytherapy):
  1. A phase III trial that randomly assigned 222 patients to undergo sublobar resection with or without suture line brachytherapy reported the following:[10]
Adjuvant chemotherapy
Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[11,12][Level of evidence: 1iiA]
Evidence (adjuvant chemotherapy for stage I NSCLC):
  1. Data on individual patient outcomes from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC were collected and pooled into a meta-analysis.[13]
    1. With a median follow-up of 5.2 years, the overall HRdeath was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.
    2. The benefit varied with stage (test for trend, P = .04; HR for stage IA, 1.40; 95% CI, 0.95–2.06; HR for stage IB, 0.93; 95% CI, 0.78–1.10; HR for stage II, 0.83; 95% CI, 0.73–0.95; and HR for stage III, 0.83; 95% CI, 0.72–0.94).
    3. The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR, 0.80; 95% CI, 0.70–0.91), etoposide or vinca alkaloid (HR, 0.92; 95% CI, 0.80–1.07), or other drugs (HR, 0.97; 95% CI, 0.84–1.13).
    4. The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with a better performance status.
    5. There was no interaction between chemotherapy effect and any of the following:
      • Sex.
      • Age.
      • Histology.
      • Type of surgery.
      • Planned radiation therapy.
      • Planned total dose of cisplatin.
  2. Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[13-19]
Although there is sufficient evidence that postoperative chemotherapy is effective in patients with stage II or stage IIIA NSCLC, its usefulness in patients with stage IB NSCLC is less clear.
Evidence (adjuvant chemotherapy for stage IB NSCLC):
  1. The Cancer and Leukemia Group B study (CALGB-9633 [NCT00002852]) addressed the results of adjuvant carboplatin and paclitaxel versus observation for OS in 344 patients with resected stage IB (i.e., pathological T2, N0) NSCLC. Within 4 to 8 weeks of resection, patients were randomly assigned to postoperative chemotherapy or observation.[20]
    • Survival was not significantly different (HR, 0.83; CI, 0.64–1.08; P = .12) at a median follow-up of 74 months.
    • Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths.
    • A post-hoc exploratory analysis demonstrated a significant survival difference in favor of postoperative chemotherapy for patients who had tumors 4 cm or larger in diameter (HR, 0.69; CI, 0.48–0.99; P = .043).
Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.[20][Level of evidence: 1iiA]

Radiation therapy

Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent.
Conventional radiation therapy
Historically, conventional primary radiation therapy consisted of approximately 60 Gy to 70 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation (1.8–2.0 Gy per day).
Prognosis:
In the largest retrospective conventional radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% to 30%.[21-23] Several series demonstrated that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 30% to 60% were found in this subgroup.[21,22,24] However, local-only failure occurs in as many as 50% of patients treated with conventional radiation therapy to doses in the range of 60 Gy to 65 Gy.[25,26]
Evidence (conventional radiation therapy):
  1. A single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery reported the following:[24]
    • Survival at 5 years after radiation therapy with curative intent was comparable with a historical control group of patients of similar age who were resected with curative intent.
  2. A small case series using matched controls reported the following:[4]
    • The addition of endobronchial brachytherapy improved local disease control compared with external-beam radiation therapy (EBRT).[4][Level of evidence: 3iiiDiii]
A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Observation and radiation therapy may be considered for these patients.[27-29] Nonrandomized observational studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only.[27,30]
Improvements in radiation techniques include planning techniques to account for tumor motion, more conformal planning techniques (e.g., 3-D conformal radiation therapy and intensity-modulated radiation therapy), and image guidance during treatment. Modern approaches to delivery of EBRT include hypofractionated radiation therapy and stereotactic body radiation therapy (SBRT).However, there are limited reliable data from comparative trials to determine which approaches yield superior outcomes.[28,29]
Hypofractionated radiation therapy
Hypofractionated radiation therapy involves the delivery of a slightly higher dose of radiation therapy per day (e.g., 2.4–4.0 Gy) over a shorter period of time compared with conventionally fractionated radiation therapy. Multiple prospective phase I/II trials have demonstrated that hypofractionated radiation therapy to a dose of 60 Gy to 70 Gy delivered over 3 to 4 weeks with 2.4 Gy to 4.0 Gy per day resulted in a low incidence of moderate to severe toxicity, 2-year OS of 50% to 60%, and 2-year tumor local control of 80% to 90%.[31-33][Level of evidence: 3iiiA]
Stereotactic body radiation therapy (SBRT)
SBRT involves the delivery of highly conformal, high-dose radiation therapy over an extremely hypofractionated course (e.g., one to five treatments) delivered over 1 to 2 weeks. Commonly used regimens include 18 Gy × 3, 12 Gy to 12.5 Gy × 4, and 10 Gy to 12 Gy × 5, and deliver a substantially higher biologically effective dose compared with historic conventional radiation therapy regimens.
Multiple prospective phase I/II trials and institutional series have demonstrated that SBRT results in a low incidence of pulmonary toxicity (<10% risk of symptomatic radiation pneumonitis), 2-year OS of 50% to 60%, and 2-year tumor control of 90% to 95%.[34-40][Level of evidence: 3iiiA]
Evidence (SBRT):
  1. Early phase I/II trials from Indiana University identified the maximum tolerated dose of three-fraction SBRT at 18 Gy × 3 for T1 tumors, and this regimen resulted in 2-year OS of 55% and 2-year local tumor control of 95%.
    • An unacceptably high incidence (8.6%) of grade 5 toxicity was observed in patients with central tumors (defined as within 2 cm of the tracheobronchial tree from the trachea to the level of the lobar bronchi).[35]
  2. A subsequent multicenter trial (RTOG-0236 [NCT00087438]) studied the 18 Gy × 3 regimen in 55 patients with peripheral T1 to T2 tumors only and demonstrated 3-year OS of 56% and 3-year primary tumor control of 98%.
    • The incidence of moderate to severe toxicity was low, with grade 3 toxicity in 24% of patients, grade 4 toxicity in 4% of patients, and no grade 5 toxicity, with a 4% incidence of grade 3 radiation pneumonitis.[39]
  3. In the largest reported series from VU University Medical Center Amsterdam, 676 patients with T1 to T2 tumors were treated with three-, five-, and eight-fraction SBRT using a risk-adapted approach (a tailored fractionation regimen based on tumor proximity to critical organs).
    • With a median follow-up of 32.9 months, the median OS was 40.7 months, and 2-year local tumor control was 95%.[40]
  4. While central location is a contraindication to three-fraction SBRT based on data from the Indiana phase II study, a subsequent systematic review of published reports of 315 patients with 563 central tumors demonstrated a much lower incidence of severe toxicity, including a 1% to 5% risk of grade 5 events with more protracted SBRT regimens (e.g., four to ten fractions).[41] A multicenter phase I/II trial (RTOG-0813[NCT00750269]) is ongoing to identify the maximum tolerated dose for a five-fraction SBRT regimen for central tumors.
Randomized trials of conventional radiation therapy versus SBRT (NCT01014130), and hypofractionated radiation therapy versus SBRT (LUSTRE [NCT01968941]) are ongoing to determine the optimal radiation therapy regimen, but stereotactic body radiation therapy has been widely adopted for patients with medically inoperable stage I NSCLC.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:
  1. Clinical trials of postoperative chemoprevention (as evidenced in the Eastern Cooperative Oncology Group (ECOG) (ECOG-5597 [NCT00008385] trial, for example).
  2. Endobronchial therapies, including photodynamic therapy, for highly selected patients with T1, N0, M0 tumors.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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