jueves, 11 de abril de 2019

Non-Small Cell Lung Cancer Treatment (PDQ®) 4/5 —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

Stages IIA and IIB NSCLC Treatment

Standard Treatment Options for Stages IIA and IIB NSCLC

Standard treatment options for stages IIA non-small cell lung cancer (NSCLC) and IIB NSCLC include the following:
  1. Surgery.
  2. Radiation therapy (for patients who cannot have surgery).
Adjuvant radiation therapy has not been shown to improve outcomes in patients with stage II NSCLC.

Surgery

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, or segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.
Evidence (surgery):
  1. 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.[1] 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).[1][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 as the result 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).
  2. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030 [NCT00003831]).[2]
    • Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]
    • There was no difference in overall survival (OS), disease-free survival (DFS), local recurrence, and regional recurrence.[3][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.[3][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 potential methodological weaknesses of the trials.
Adjuvant chemotherapy
The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.
After surgery, many patients develop regional or distant metastases.[4] Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[5-11]
Evidence (adjuvant chemotherapy):
  1. Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[7]
    • With a median follow-up time 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.
    • 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).
    • 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).
    • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted cautiously as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  2. The meta-analysis [7] and the individual studies [5,12] support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.
    1. Superior OS for the trial population and patients with stage II disease was reported for the Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis (pooled HR, 0.83; 95% CI, 0.73–0.95); the Adjuvant Navelbine International Trialist Association (ANITA) trial (HR, 0.71; 95% CI, 0.49–1.03); and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial (HR, 0.59; 95% CI, 0.42–0.85).
    2. Chemotherapy effect was higher in patients with better performance status (PS).
    3. 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.
  3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[13]
    • Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
    • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.[13]
  4. Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[5-11]
Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[13][Level of evidence: 1iiA]
Neoadjuvant chemotherapy
The role of chemotherapy before surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include the following:
  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.
Preoperative chemotherapy may, however, delay potentially curative surgery.
Evidence (neoadjuvant chemotherapy):
  1. The Cochrane Collaboration reported a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone. These trials evaluated patients with stages I, II, and IIIA NSCLC.[14]
    • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[14][Level of evidence: 1iiA]
    • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.
  2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease; and 7% had stage III disease.[15]
    • No survival advantage was seen.[15]
    • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
    • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
    • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant (preoperative) chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.
Adjuvant radiation therapy
The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[16]
Evidence (adjuvant radiation therapy):
  1. A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[16]
    • 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.[16][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.

Radiation therapy

Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[17] Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.
Prognosis:
Among patients with excellent PS, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.
Evidence (radiation therapy):
  1. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC were treated with definitive radiation therapy. The study reported the following:[18]
    • A 5-year OS rate of 10%.
    • Forty-four patients with T1 tumors achieved an actuarial DFS rate of 60%.
    • This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.[18]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:
  1. Clinical trials of radiation therapy after curative 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.
References
  1. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005. [PUBMED Abstract]
  2. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006. [PUBMED Abstract]
  3. Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011. [PUBMED Abstract]
  4. Martini N, Bains MS, Burt ME, et al.: Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 109 (1): 120-9, 1995. [PUBMED Abstract]
  5. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005. [PUBMED Abstract]
  6. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004. [PUBMED Abstract]
  7. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
  8. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003. [PUBMED Abstract]
  9. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004. [PUBMED Abstract]
  10. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992. [PUBMED Abstract]
  11. 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]
  12. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006. [PUBMED Abstract]
  13. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007. [PUBMED Abstract]
  14. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007. [PUBMED Abstract]
  15. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007. [PUBMED Abstract]
  16. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
  17. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
  18. Dosoretz DE, Katin MJ, Blitzer PH, et al.: Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys 24 (1): 3-9, 1992. [PUBMED Abstract]

Stage IIIA NSCLC Treatment

Patients with stage IIIA non-small cell lung cancer (NSCLC) are a heterogenous group. Patients may have metastases to ipsilateral mediastinal nodes, potentially resectable T3 tumors invading the chest wall, or mediastinal involvement with metastases to peribronchial or hilar lymph nodes (N1). Presentations of disease range from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal stations.
Prognosis:
Patients with clinical stage IIIA N2 disease have a 5-year overall survival (OS) rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.
Treatment options vary according to the location of the tumor and whether it is resectable.

Standard Treatment Options for Resected/Resectable Stage IIIA N2 NSCLC

Despite careful preoperative staging, some patients will be found to have metastases to mediastinal N2 lymph nodes at thoracotomy.
Standard treatment options for resected/resectable disease include the following:
  1. Surgery.
  2. Neoadjuvant therapy.
  3. Adjuvant therapy.
The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

Surgery

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (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.[1][Level of evidence: 1iiA]
The addition of surgery to chemoradiation therapy for patients with stage IIIA NSCLC did not result in improved OS in a phase III trial but did improve progression-free survival (PFS) and local control.[2][Level of evidence: 1iiDiii]
Evidence (surgery):
  1. 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.[3] 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 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).[3][Level of evidence: 1iiA]
  2. CMLND versus lymph node sampling was evaluated in a large randomized phase III trial (ACOSOG-Z0030). Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[4]
    • There was no difference in OS, disease-free survival (DFS), local recurrence, and regional recurrence.[1][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 by the potential methodological weaknesses of the trials.

Neoadjuvant therapy

Neoadjuvant chemotherapy
The role of chemotherapy before surgery in patients with stage III N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include the following:
  • A reduction in tumor size that may facilitate surgical resection.
  • Early eradication of micrometastases.
  • Better tolerability.
Evidence (neoadjuvant chemotherapy):
  1. The Cochrane Collaboration provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.[5] These trials evaluated patients with stages I, II, and IIIA NSCLC.
    • Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[5][Level of evidence: 1iiA]
    • This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[6]
  2. In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery.[7] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease.
    • Postoperative complications were similar between groups, and no impairment of quality of life was observed.
    • There was no evidence of a benefit in terms of OS (HR, 1.02; 95% CI, 0.80–1.31; P = .86).
    • Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of preoperative chemotherapy (1,507 patients, HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[7]
Neoadjuvant chemoradiation therapy
Administering concurrent neoadjuvant chemotherapy and radiation therapy before surgery may intensify treatment and increase the likelihood of downstaging the tumor burden. Commonly utilized regimens that have been tested in the phase II setting include cisplatin/etoposide (EP5050) and weekly carboplatin/paclitaxel.[8,9] In a randomized trial of neoadjuvant chemoradiation therapy and surgery versus concurrent chemoradiation therapy alone, there was no difference in OS, but surgery improved PFS and local control.[2][Level of evidence: 1iiDiii]
Evidence (neoadjuvant chemoradiation therapy):
  1. The Intergroup-0139 [NCT00002550] trial compared chemoradiation therapy alone with neoadjuvant chemoradiation followed by surgery in 396 patients with stage IIIA NSCLC.[2]
    • Surgery did not improve OS (5-year OS, 27% vs. 20%; HR: 0.87 [0.70–1.10]; P = .24).
    • Surgery improved PFS (5-year PFS, 22% vs. 11%; HR 0.77 [0.62–0.96]; P = .017) and decreased the risk of local recurrence (10% vs. 22%; P = .002).
    • There was increased treatment mortality with neoadjuvant chemoradiation with surgery (8% vs. 2%), particularly in the subset of patients who underwent pneumonectomy.
A direct comparison of neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy using modern treatment regimens has not been performed to date; the optimal neoadjuvant approach remains unclear.

Adjuvant therapy

Adjuvant chemotherapy
Patients with completely resected stage IIIA NSCLC may benefit from postoperative cisplatin-based chemotherapy.[10][Level of evidence: 1iiA]
Evidence (adjuvant chemotherapy):
Evidence from randomized controlled clinical trials indicates that when stage IIIA NSCLC is encountered unexpectedly at surgery, chemotherapy given after complete resection improves survival.
Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[10-16]
  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.[10]
    • 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.
    • 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).
    • The benefit varied with stage (HR for stage IIIA, 0.83; 95% CI, 0.72–0.94).
    • The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.
  2. Two trials (FRE-IALT and the Adjuvant Navelbine International Trialist Association [ANITA] trial) reported significant OS benefits associated with postoperative chemotherapy in stage IIIA disease.[6,12]
    1. For the subgroup of stage IIIA patients in the ANITA trial (n = 325), the HR was 0.69 (95% CI, 0.53–0.90), and the result for the FRE-IALT trial (n = 728) was HR, 0.79 (95% CI, 0.66–0.95).
    2. The chemotherapy effect was higher in patients with a better performance status (PS).
    3. There was no interaction between the chemotherapy effect and any of the following:
      • Sex.
      • Age.
      • Histology.
      • Type of surgery.
      • Planned radiation therapy.
      • Planned total dose of cisplatin.
  3. In a retrospective analysis of a phase III trial of postoperative cisplatin and vinorelbine, patients older than 65 years were found to benefit from treatment.[17]
    • Chemotherapy significantly prolonged OS for elderly patients (HR, 0.61; 95% CI, 0.38–0.98; P = .04).
    • There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.
Adjuvant chemoradiation therapy
Combination chemotherapy and radiation therapy administered before or following surgery should be viewed as investigational and requiring evaluation in future clinical trials.
Evidence (adjuvant chemoradiation therapy):
  1. Five randomized trials have assessed the value of postoperative combination chemoradiation therapy versus radiation therapy following surgical resection.[5,7,18-20][Level of evidence: 1iiA]
    • Only one trial reported improved DFS and no trial reported improved OS.
  2. Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus platinum-based chemotherapy followed by radiation therapy (60–69.6 Gy) alone to determine whether surgery or radiation therapy was most efficacious.[20-22] Although the studies were small, enrolling 73 (Radiation Therapy Oncology Group [RTOG]) (RTOG 89-01), 107 (The University of Texas M.D. Anderson Cancer Center), and 333 (European Organization for Research and Treatment of Cancer [EORTC-08941; NCT00002623]) patients with stage IIIA N2 disease, no trial reported a difference in local control or survival.[20-22][Level of evidence: 1iiA]
    1. In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA N2 NSCLC were given three cycles of platinum-based induction chemotherapy.[22] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 patients (92%) who underwent surgery, 50% had a radical resection, 42% had a pathologic downstaging, and 5% had a pathologic complete response; 4% died after surgery. Postoperative (adjuvant) radiation therapy (PORT) was administered to 62 patients (40%) in the surgery arm. Among the 154 patients (93%) who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3 to 4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.
      • Median OS was 16.4 months for patients assigned to resection versus 17.5 months for patients assigned to radiation therapy; 5-year OS was 15.7% for patients assigned to resection versus 14% for patients assigned to radiation therapy (HR, 1.06; 95% CI, 0.84–1.35).[22]
      • Rates of PFS were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.[22]
Adjuvant radiation therapy
The value of PORT has been assessed.[18] Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.[18]
As referred to in the National Cancer Institute of Canada (NCIC) Clinical Trials Group JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:[17]
  • Involvement of multiple nodal stations.
  • Extracapsular tumor spread.
  • Close or microscopically positive resection margins.
Evidence (adjuvant radiation therapy):
Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.
  1. A meta-analysis of ten randomized trials that evaluated PORT versus surgery alone showed the following:
  2. Results from a nonrandomized subanalysis of the ANITA trial, comparing 5-year OS in N2 patients who did or did not receive PORT, found the following:[6]
    • Higher survival rates in patients who received radiation therapy in the observation arm (21% in patients who received PORT vs. 17% in patients who did not receive PORT) and in the chemotherapy arm (47% with PORT vs. 34% without PORT); however, statistical tests of comparison were not conducted.[6]
  3. Results from the Surveillance, Epidemiology, and End Results (SEER) program [19] suggest the following:
    • The large SEER retrospective study (N = 7,465) found superior survival rates associated with radiation therapy in N2 disease (HR, 0.855; 95% CI, 0.762–0.959).
There is benefit of PORT in stage IIIA N2 disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[12]

Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC

Standard treatment options for patients with unresectable NSCLC include the following:
  1. Radiation therapy.
  2. Chemoradiation therapy.

Radiation therapy

For treatment of locally advanced unresectable tumor
Radiation therapy alone, administered sequentially with chemotherapy and concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC.
Prognosis:
Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[23]
Evidence (radiation therapy for locally advanced unresectable tumor):
  1. One prospective randomized clinical study showed the following:[24]
    • Radiation therapy given continuously (including weekends) as three daily fractions (continuous hyperfractionated accelerated radiation therapy) improved OS compared with radiation therapy given as one daily fraction.[24][Level of evidence: 1iiA]
    • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.
Although patients with unresectable stage IIIA disease may benefit from radiation therapy, long-term outcomes have generally been poor because of local and systemic relapse.
For patients requiring palliative treatment
Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:
  • Tracheal, esophageal, or bronchial compression.
  • Pain.
  • Vocal cord paralysis.
  • Hemoptysis.
  • Superior vena cava syndrome.
In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[25]
Evidence (radiation therapy for palliative treatment):
  1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[26]
    • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[26][Level of evidence: 1iiC]
    • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
    • For EBRT, different multifraction regimens appear to provide similar symptom relief;[27-32] however, single-fraction radiation therapy may be insufficient for symptom relief compared with hypofractionated or standard regimens, as seen in the NCIC Clinical Trials Group trial (NCT00003685).[29][Level of evidence: 1iiC]
    • Evidence of a modest increase in survival in patients with better PS given high-dose EBRT is available.[27,28][Level of evidence: 1iiA]
    • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Chemoradiation therapy

The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with an increase in toxic effects.
Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[33]
Evidence (chemoradiation therapy):
  1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[34]
    • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[34][Level of evidence: 1iiA]
  2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[35]
    • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% CI, 0.88–0.98; P = .01).
    • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[35]
  3. A meta-analysis of individual data from 1,764 patients was based on nine trials and showed the following:[33]
    • The HRdeath among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02), corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
    • The combination of platinum with etoposide appeared to be more effective than platinum alone.
Concurrent versus sequential chemoradiation therapy
The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[36-38][Level of evidence: 1iiA]
Evidence (concurrent vs. sequential chemoradiation therapy):
  1. In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[36]
    • Five-year OS favored concurrent therapy (27% vs. 9%).
    • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[36]
  2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 63 Gy of radiation therapy, concurrent chemoradiation therapy using the same regimen, or concurrent chemotherapy with cisplatin and etoposide with twice-daily radiation therapy.[38]
    • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen [P = .046]).[38]
  3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[37,39][Level of evidence: 1iiA]
  4. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[35]
    • The analysis indicated a significant benefit of concurrent over sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All studies used cisplatin-based regimens and once-daily radiation therapy.[35]
    • More deaths (3% OS rate) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
    • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.
Radiation therapy dose escalation for concurrent chemoradiation
With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[40-42] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P =.0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[43][Level of evidence: 1iiA]
Choice of systemic therapy for concurrent chemoradiation
Evidence (systemic therapy for concurrent chemoradiation):
  1. The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed, stage IIIA/B, unresectable, nonsquamous NSCLC.[44] Patients were randomly assigned on a 1:1 ratio to either of two arms:
    • Arm A: Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) intravenously every 3 weeks for three cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles.
    • Arm B: Standard therapy with etoposide (50 mg/m2) and cisplatin (50 mg/m2) intravenously every 4 weeks for two cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy.
    The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).
    • Enrollment was stopped early because of futility.
    • OS in arm A was not superior to arm B (HR, 0.98; 95% CI, 0.79–1.20; median, 26.8 vs. 25.0 months; P = .831).
    • Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001), including neutropenia (24.4% vs. 44.5%; P < .001), during the overall treatment period.
Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[45][Level of evidence: 1iiA]
Consolidation Immunotherapy
Durvalumab
Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[46]
Evidence (durvalumab):
  1. The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[46] The coprimary endpoints were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).
    • At the interim analysis, the coprimary endpoint of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P< .001).[46][Level of evidence:1iiDiii] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.
    • PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. Epidermal growth factor receptor (EGFR) mutations were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the EGFR-mutated subgroup was 0.76 (95% CI, 0.35–1.64).
    • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of the patients receiving durvalumab and in 3.8% of the patients receiving placebo.
    • OS was not assessed at the interim analysis.
Other systemic consolidation therapies
Randomized trials of other consolidation systemic therapies, including docetaxel,[47] gefitinib,[48] and tecemotide (MUC1 antigen-specific immunotherapy) [49] have not shown an improvement in OS.[Level of evidence: 1iiA]

Standard Treatment Options for Superior Sulcus Tumors (T3, N0 or N1, M0)

Standard treatment options for superior sulcus tumors include the following:
  1. Radiation therapy alone.
  2. Surgery.
  3. Chemoradiation therapy followed by surgery.
NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[50,51] Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.
Adverse prognostic factors include the presence of mediastinal nodal metastases (N2 disease), spine or subclavian-vessel involvement (T4 disease), and limited resection (R1 or R2).

Radiation therapy alone

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.[50,51]
Prognosis:
Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en-bloc resection was shown to be potentially curative.
Evidence (radiation therapy):
  1. In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[50,51]

Surgery

Evidence (surgery):
  1. Retrospective case series have reported that complete resection was achieved in only 64% of T3, N0 tumors and 39% of T4, N0 tumors.[52]

Chemoradiation therapy followed by surgery

Evidence (chemoradiation therapy):
  1. Two large, prospective, multicenter phase II trials have evaluated induction chemoradiation therapy followed by resection.[53,54]
    1. In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.[54] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.
      • The induction regimen was well tolerated, and only five participants had grade 3 or higher toxic effects.
      • Induction chemoradiation therapy could sterilize the primary lesion. Induction therapy was completed by 104 patients (95%). Of the 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resections.
      • Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Pathologic complete response led to better survival than when any residual disease was present (P = .02).
      • Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Disease progression occurred mainly in distant sites.
    2. In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[53] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%).
      • There were 12 patients with pathologic complete response.
      • Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths.
      • At 3 years, the DFS rate was 49%, and the OS rate was 61%; at 5 years, the DFS rate was 45%, and the OS rate was 56%.[53][Level of evidence: 3iiiDi]
Radiation therapy dose escalation for concurrent chemoradiation
With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[40-42] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003). Thus, there is no clear benefit in radiation dose escalation beyond 60 Gy for stage III NSCLC.[43][Level of evidence: 1iiA]
Choice of systemic therapy for concurrent chemoradiation
Evidence (systemic therapy for concurrent chemoradiation):
  1. The randomized phase III PROCLAIM study [NCT00686959] enrolled 598 patients with newly diagnosed stage IIIA/B unresectable nonsquamous NSCLC.[44] Patients were randomly assigned in a 1:1 ratio to either of two arms:
    • Arm A: Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) intravenously every 3 weeks for three cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles.
    • Arm B: Standard therapy with etoposide (50 mg/m2) and cisplatin (50 mg/m2) intravenously every 4 weeks for two cycles plus concurrent thoracic radiation therapy (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy.
    The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS HR of 0.74 with a type 1 error of .05. This study randomly assigned 598 patients (arm A, 301; arm B, 297) and treated 555 patients (arm A, 283; arm B, 272).
    • Enrollment was stopped early because of futility.
    • OS in arm A was not superior to arm B (HR, 0.98; 95% CI, 0.79–1.20; median, 26.8 vs. 25.0 months; P = .831).
    • Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001), including neutropenia (24.4% vs. 44.5%; P < .001), during the overall treatment period.
Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[45][Level of evidence: 1iiA]
The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Randomized trials of consolidation systemic therapy including docetaxel,[47] gefitinib,[48] and tecemotide (MUC1 antigen-specific immunotherapy) [49] have not shown an improvement in OS.[Level of evidence: 1iiA]

Standard Treatment Options for Tumors That Invade the Chest Wall (T3, N0 or N1, M0)

Standard treatment options for tumors that invade the chest wall include the following:
  1. Surgery.
  2. Surgery and radiation therapy.
  3. Radiation therapy alone.
  4. Chemotherapy combined with radiation therapy and/or surgery.
Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.
Evidence (radical surgery):
  1. In a small case series of 97 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 44.2%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 40.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 6.2%.[55][Level of evidence: 3iiiDi]
  2. In a small case series of 104 patients, the 5-year survival rate of patients who had completely resected T3, N0, M0 disease was 67.3%. For patients with completely resected T3, N1, M0 disease, the 5-year survival rate was 100.0%. In patients with completely resected T3, N2, M0 disease, the 5-year survival rate was 17.9%.[56][Level of evidence: 3iiiDi]
  3. In a case series of 309 patients treated at three centers, patients who underwent en bloc resection had superior outcomes compared with patients who underwent extrapleural resections (60.3% vs. 39.1%; P = .03).[57][Level of evidence: 3iiiDi]
Adjuvant chemotherapy is recommended and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined-modality approaches have been evaluated to improve ability to achieve complete resection.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:
  1. Combined modality therapy, including chemotherapy, radiation therapy, and surgery in various combinations.

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.
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