Non-Small Cell Lung Cancer Treatment (Professional) (cont.)
Stage II NSCLC Treatment
Standard Treatment Options for Stage II NSCLC
Standard treatment options for stage II NSCLC include the following:
- Neoadjuvant chemotherapy.
- Adjuvant chemotherapy.
- Radiation therapy.
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.
- 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 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).
- 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 potential methodological weaknesses of the trials.
The role of chemotherapy prior to 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.
- The Cochrane Collaboration Review group 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.
- 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).[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.
- 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.
- No survival advantage was seen.
- 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 overall survival (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.
- 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.
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. Several randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7,8,9,10,11,12,13]
- 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 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.
- The meta-analysis as well as the individual studies [7,14] support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.
- The LACE pooled analysis (NCT00576914), ANITA trial, and NCIC-CTG JBR.10 trial (NCT00002583) all reported superior OS for the trial population as well as for the patients with stage II disease (pooled HR = 0.83, 95% CI, 0.73–0.95; HR = 0.71, 95% CI, 0.49–1.03; HR = 0.59, 95% CI, 0.42–0.85, respectively).
- Chemotherapy effect was higher in patients with better performance status (PS).
- There was no interaction between chemotherapy effect and any of the following:
- Type of surgery.
- Planned radiation therapy.
- Planned total dose of cisplatin.
- 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.
- 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.
- Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7,8,9,10,11,12,13]
Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[Level of evidence: 1iiA]
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. 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.
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.
- 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:
- A 5-year OS rate of 10%.
- Forty-four patients with T1 tumors achieved an actuarial disease-free survival (DFS) rate of 60%.
- This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.
Treatment Options Under Clinical Evaluation
Treatment options under clinical evaluation for stage II NSCLC include the following:
- Clinical trials of radiation therapy after curative surgery.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II 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.
- Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005.
- 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.
- 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.
- 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.
- PORT Meta-analysis Trialists Group.: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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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