Case study 76.1
A 55-year-old woman, a lifetime nonsmoker, was diagnosed with a 6 cm spiculated right upper lobe lung nodule. Staging showed no evidence of distant metastatic disease. She underwent a right upper lobectomy. The surgical pathology report indicated a T2bN0M0 well-differentiated lung adenocarcinoma (stage IIA, AJCC version 7). Surgical resection margins were negative, and there was no evidence of lymphovascular space invasion. Molecular analysis revealed an activating epidermal growth factor receptor (EGFR) mutation (exon 19 deletion).
1. How should she be managed after surgery?
- She should receive adjuvant cisplatin-based chemotherapy for four cycles followed by chest radiotherapy
- She should complete four cycles of cisplatin-based chemotherapy followed by two years of an EGFR tyrosine kinase inhibitor (TKI)
- She should only receive an EGFR TKI for 2 years
- She should receive four cycles of adjuvant cisplatin-based chemotherapy
- She should be scheduled for ongoing surveillance only
After surgical excision with curative intent, the 5-year survival for pathological stage IIA non-small-cell lung cancer (NSCLC) is 46%. Adjuvant chemotherapy prolongs survival in patients with resected stage II and III NSCLC based on long-term follow-up results of two phase III clinical trials and a recent meta-analysis. While there is clear evidence to recommend adjuvant cisplatin-based chemotherapy for those with resected N1 or N2 disease, the value of adjuvant chemotherapy, in the absence of pathological evidence of lymph node metastasis (N0), remains the subject of debate.
The Cancer and Leukemia Group B (CALGB) 9633 randomized trial investigated the role of adjuvant chemotherapy in completely resected T2N0 tumors (Stage IB; AJCC cancer staging manual, 6th ed.). Upon final analysis, while there was no statistically significant difference between the observation and chemotherapy arms in this small trial, exploratory analysis suggested that patients with tumors ≥4.0 cm may benefit from adjuvant carboplatin and paclitaxel chemotherapy (P = 0.043). A similar exploratory analysis of the NCIC Clinical Trials Group JBR.10 randomized trial demonstrated that the subgroup of patients with node-negative tumors ≥4 cm derived clinically meaningful benefit from cisplatin-based adjuvant chemotherapy (hazard ratio (HR): 0.66). Thus, many clinicians do offer adjuvant cisplatin-based therapy to fit patients with completely resected lymph node negative NSCLC if the tumor size is ≥4 cm.
The role of EGFR-activating mutations as predictors of EGFR TKI response in patients with metastatic NSCLC is well established. Five randomized phase III trials have prospectively compared the efficacy of initial EGFR TKI therapy to standard platinum-based chemotherapy in patients with EGFR mutation–positive advanced NSCLC: the West Japanese WJTOG3405, North-East Japan Study Group (NEJ002), OPTIMAL-CTONG-0802, EURTAC, and LUX-LUNG3 studies. In all trials, patients treated with EGFR TKI had significantly better progression-free survival (PFS), response rate (RR), symptom relief, or quality of life than patients treated with platinum-based chemotherapy. However, the prognostic and predictive value of the EGFR mutation in resected early-stage NSCLC remains less clear. At least three retrospective analyses demonstrated that patients with resected EGFR mutation–positive NSCLC had a better prognosis compared to those with EGFR wild-type tumors. In the NCIC Clinical Trials Group BR.19 adjuvant intergroup trial, patients with completely resected stage IB–IIIA, otherwise unselected, NSCLC were randomized to receive gefitinib or placebo for up to 2 years. The study was later amended to allow adjuvant cisplatin-based chemotherapy (stratified) as appropriate prior to a gefitinib or placebo start. Unfortunately, this trial was prematurely closed after 503 patients had been randomized because of the negative SWOG S0023 trial, where maintenance gefitinib after chemoradiation in locally advanced NSCLC yielded worse survival than placebo. Analysis of the underpowered NCIC CTG BR.19 trial did not show any difference between adjuvant gefitinib and placebo. In addition, neither KRAS mutation status nor EGFR copy number by fluorescence in situ hybridization (FISH) or EGFR mutation status had prognostic or predictive value. Of 503 patients, 357 had EGFR genotyping performed, and 21% had EGFR mutation–positive tumors. The HR for survival in the gefitinib arm was 1.58 (95% confidence interval (CI): 0.83 to 3.00; log-rank P-value = 0.160). Median survival in the EGFR mutation–positive subgroup receiving adjuvant gefitinib was 3.7 years, and it was 5.1 years for those receiving placebo. Interestingly, multivariate analysis indicated that never smokers, a group with a high incidence of sensitizing EGFR mutations, had longer survival with gefitinib in this study (P = 0.02). A retrospective cohort analysis at a single institution suggested that survival outcomes of early-stage EGFR mutation–positive NSCLC patients were longer if they received adjuvant EGFR TKI than if they did not. Interestingly, a subgroup analysis of the NCIC CTG JBR.10 study suggested longer survival and greater chemotherapy benefit in those with exon 19 and 21 EGFR mutations compared to EGFR wild type, although these differences were not statistically significant.
The hypothesis that patients with EGFR mutant NSCLC derive clinically significant benefit from adjuvant treatment with EGFR TKI therapy remains compelling, and the existing data does not support routine use of EGFR TKI as adjuvant treatment outside a clinical trial at this time. The RADIANT trial of adjuvant erlotinib versus placebo in resected stage IB–IIIA NSCLC has completed accrual. While initial results are pending, a preliminary assessment indicates that 14% of participants have EGFR mutant tumors. In the WJTOG6410L study, which is led by Japanese investigators, patients with resected EGFR mutation-positive NSCLC are randomized to four cycles of vinorelbine–cisplatin versus gefitinib. Those with classic EGFR exon 19 deletion or L858R exon 21 insertion mutations are eligible; those with tumors harboring T790M mutations conferring resistance to EGFR TKIs are excluded. Results of this randomized study will shed more light on the role of adjuvant EGFR TKI therapy in patients with EGFR-sensitizing mutations.
In summary, patients with completely resected stage II and III NSCLC should be offered adjuvant cisplatin-based chemotherapy. This recommendation extends to those with node-negative tumors where the primary tumor size is ≥4 cm. At present, there is insufficient data to recommend adjuvant EGFR TKI therapy in those with resected NSCLC harboring EGFR mutations. These patients should be considered for adjuvant chemotherapy if appropriate.
17: Management of Therapy-Related Myeloid Neoplasms
36: Nodular Lymphocyte-Predominant Hodgkin Lymphoma
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
