Non-Small Cell Lung Cancer Treatment (Professional) (cont.)
Stage I NSCLC Treatment
Standard Treatment Options for Stage I NSCLC
Standard treatment options for stage I NSCLC include the following:
- Radiation therapy.
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.
- 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:
- A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.
- No significant difference in overall survival (OS).
- Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.
- 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.
- A study of stage I patients showed the following:
- 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.
- The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer. 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).[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).
- Current evidence suggests that lung cancer resection combined with CMLND is associated with a small to modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[Level of evidence: 1iiA]
- 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.
Limitations of evidence:
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.
Many patients treated surgically subsequently develop regional or distant metastases. 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.
- A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:
- 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.[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.
Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[9,10][Level of evidence: 1iiA]
- 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.
- With a median follow-up time of 5.2 years, the overall HR of death 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 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.
- There was no interaction between chemotherapy effect and any of the following:
- Type of surgery.
- Planned radiation therapy.
- Planned total dose of cisplatin.
- Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[11,12,13,14,15,16,17]
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.
- The Cancer and Leukemia Group B study (CALGB-9633) 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.
- 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 greater 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. [Level of evidence: 1iiA]
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. Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor volume 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.
In the two largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%.[19,20] Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.
- 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: 
- 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.
- A small case series using matched controls reported the following: 
- The addition of endobronchial brachytherapy improved local disease control compared with external-beam radiation therapy.[Level of evidence: 3iiiDiii]
Treatment Options Under Clinical Evaluation
Treatment options under clinical evaluation for stage I NSCLC include the following:
- Clinical trials of postoperative chemoprevention (as evidenced in the ECOG-5597 trial, for example).
- Endobronchial therapies, including photodynamic therapy, for highly selected patients with T1, N0, M0 tumors.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Ginsberg RJ, Hill LD, Eagan RT, et al.: Modern thirty-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86 (5): 654-8, 1983.
- Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60 (3): 615-22; discussion 622-3, 1995.
- Warren WH, Faber LP: Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 107 (4): 1087-93; discussion 1093-4, 1994.
- Mantz CA, Dosoretz DE, Rubenstein JH, et al.: Endobronchial brachytherapy and optimization of local disease control in medically inoperable non-small cell lung carcinoma: a matched-pair analysis. Brachytherapy 3 (4): 183-90, 2004.
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- 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.
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- PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
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- 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.
- 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.
- 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.
- 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.
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- 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.
- Strauss GM, Herndon JE 2nd, Maddaus MA, et al.: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26 (31): 5043-51, 2008.
- 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.
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- Noordijk EM, vd Poest Clement E, Hermans J, et al.: Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 13 (2): 83-9, 1988.
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