Key points

Background

Lung cancer cure rates have increased slowly over the last decades, despite tremendous advances in our understanding of the molecular biology of the disease, screening, and improvements in local therapy options. Median 5-year survival rate, as an indicator of cure rates, ranges from just more than 50% for stage IA disease to less than 30% for stage IIIA disease.

For the early stages of disease, complete surgical resection remains the most effective initial therapy for patients. Recent data also support the use of stereotactic radiation therapy in patients who are not good operative candidates, although trials to compare it with surgery in operative candidates suffer from poor accrual, leaving that question unanswered. Multiple attempts to improve outcomes from surgery with the addition of chemotherapy either before (neoadjuvant) or after (adjuvant) use of targeted therapies and postoperative radiation have been investigated.

Background

Lung cancer cure rates have increased slowly over the last decades, despite tremendous advances in our understanding of the molecular biology of the disease, screening, and improvements in local therapy options. Median 5-year survival rate, as an indicator of cure rates, ranges from just more than 50% for stage IA disease to less than 30% for stage IIIA disease.

For the early stages of disease, complete surgical resection remains the most effective initial therapy for patients. Recent data also support the use of stereotactic radiation therapy in patients who are not good operative candidates, although trials to compare it with surgery in operative candidates suffer from poor accrual, leaving that question unanswered. Multiple attempts to improve outcomes from surgery with the addition of chemotherapy either before (neoadjuvant) or after (adjuvant) use of targeted therapies and postoperative radiation have been investigated.

Adjuvant chemotherapy

Although the benefit of adjuvant chemotherapy in other malignancies has been known for decades, this approach in non–small cell lung cancer (NSCLC) has only been a standard since positive trial results in 2003. Earlier outcome data and case series from single academic centers were viewed with some skepticism given concerns of selection bias. In 1995, an individual patient meta-analysis published by the Non–Small Cell Lung Cancer Collaborative Group (NSCLCCG) reported a survival detriment with the earliest adjuvant trials, which used long-term alkylating agent-based regimens. But the cisplatin-based regimens adopted in the early 1980s showed more promise. Analysis of data from more than 1300 patients enrolled in 8 trials of adjuvant cisplatin-based therapy showed a trend toward survival benefit at 5 years with a 5% improvement over observation (overall survival hazard ratio [OS HR], 0.87; 95% confidence interval [CI], 0.74–1.02, P = .08). Multiple randomized phase III trials followed to confirm these results, although results of the first trials were negative. The Eastern Cooperative Oncology Group 3590 (Intergroup 0115) study, the European Big Lung Trial, and the Adjuvant Lung Project Italy (ALPI) all failed to show a survival benefit, although they were well-conducted, randomized, phase III trials of adjuvant cisplatin-based regimens. In these trials, patients with completed resected NSCLC were randomly assigned to approximately 3 months of cisplatin-based chemotherapy, initiated within 2 months of surgical resection. ALPI was large enough (1209 patients) to detect a benefit such as what was seen in the NSCLCCG meta-analysis, but the study was negative with an OS HR of 0.96 (95% CI, 0.81–1.13; P = .589).

Starting in 2003, other studies started to detect the level of benefit predicted in the meta-analysis. The International Adjuvant Lung Cancer Trial (IALT) (n = 1867) reported in 2004 a 4% 5-year survival benefit (44.5% vs 40.4%) and an OS HR of 0.86 (95% CI, 0.76–0.98; P <.03). Patients enrolled on this trial were randomly assigned to observation or adjuvant chemotherapy with cisplatin and either etoposide, vindesine, or vinblastine. In 2009, the long-term follow-up results were presented with an OS HR of 0.91 (95% CI, 0.81–1.02; P = .10), although the disease-free survival (DFS) benefit persisted (HR, 0.88; 95% CI, 0.78–0.98; P = .02). These results, however, did not alter the use of adjuvant cisplatin-based chemotherapy, especially in light of other positive studies.

Two other adjuvant chemotherapy trials maintained the significantly improved survival benefits even with long-term follow-up. These trials used only the cisplatin/vinorelbine doublet. The National Cancer Institute of Canada Clinical Trials Group JBR.10 trial enrolled 482 completed resected stage IB-II patients in North America and has continued to show a significant survival advantage for adjuvant chemotherapy group compared with observation with a median of 9.3 years of follow-up (HR, 0.78; 95% CI, 0.61–0.99; P = .04). The absolute survival benefit at 5 years was 11% in the final analysis of JBR.10. The Adjuvant Navelbine International Trialist Association (ANITA) study randomly assigned 840 patients (39% stage IIIA) with an OS HR of 0.80 (95% CI, 0.66–0.96; P = .017) and an absolute OS benefit favoring the chemotherapy group at 5 years of 8.6%.

Two large meta-analyses were conducted on the studies discussed above. The Lung Adjuvant Cisplatin Evaluation (LACE) analysis included 4584 patients from ALPI, IALT, ANITA, JBR.10, and the European Big Lung Trial. The authors reported a 5.4% absolute survival benefit at 5 years, with a median of 5.1 years of follow-up, corresponding to an OS HR of 0.89 (95% CI, 0.82–0.96; P = .005) in favor of the chemotherapy arm. When broken down by stage, no benefit was found for stage IA (OS HR, 1.41; 95% CI, 0.96–2.09) or stage IB (OS HR, 0.93; 95% CI, 0.78–1.10). In patients with lymph node involvement, however, the benefit was significant with both stage II and III groups having an OS HR of 0.83 (95% CI, 0.73–0.95). The updated NSCLCCG postoperative chemotherapy meta-analysis included individual data on 8447 patients and also confirmed the 4% absolute survival increase (95% CI, 3%–6%) at 5 years from 60% to 64% (HR, 0.86; 95% CI, 0.81–0.92; P <.0001). Guidelines continue to endorse the use of adjuvant cisplatin-based chemotherapy for stage II and IIIA NSCLC after complete resection, supported by the results of the 2 meta-analyses.

The use of adjuvant cisplatin-based chemotherapy doublets for patients with stage I NSCLC remains controversial. Many studies and clinical practice use a 4-cm cut-point for adjuvant chemotherapy, based on subset analyses of 2 trials. When the stage IB patients in JBR.10 were divided into those with tumors at least 4 cm in size and those with smaller tumors, the OS HR was 1.73( P = .06) for the smaller tumors (<4 cm) but OS HR was 0.66 ( P = .13) for the larger tumors, implying potential chemotherapy benefit. The OS HR for the patients with tumors at least 4 cm in size was also 0.66 ( P = .04) in a similar analysis done from CALGB9633 (further described in detail below). A more recent retrospective analysis of nearly 30,000 patients from the National Cancer Database also showed improved median and 5-year survival in patients with resected T2N0M0 NSCLC who received adjuvant chemotherapy compared with those who did not. In the National Cancer Database analysis, the benefit of adjuvant chemotherapy was even seen in patients with tumor 3.1 to 3.9 cm in size.

Chemotherapy choice

Other controversy surrounds the use of the chemotherapeutic agent to pair with cisplatin. In the LACE meta-analysis, cisplatin/vinorelbine was associated with a substantially superior survival benefit compared with the other regimens used. In a small phase II adjuvant trial, cisplatin/pemetrexed was better tolerated than cisplatin/vinorelbine, but efficacy data were inconclusive. Recent data from the large adjuvant trial E1505 confirm that, given a choice, many practitioners in the United States prefer other platinum doublets. The E1505 trial found that investigators were choosing from among all 4 chemotherapy options (cisplatin/vinorelbine 25%, cisplatin/gemcitabine 19%, cisplatin/docetaxel 23%, and cisplatin/pemetrexed 33%). A subset analysis found no significant differences in outcome among the 4 regimens, although cisplatin/pemetrexed resulted in less grade 3/4/5 toxicity overall compared with the others. Nevertheless, the study was not randomized for chemotherapy choice and was not powered for this subset analysis. The ongoing JIPANG trial in Japan is randomly assigning patients to cisplatin/pemetrexed or cisplatin/vinorelbine and will provide prospective data to better resolve the question of whether there is a meaningful difference based on which chemotherapy doublet is used.

Limited data exist to support the substitution of carboplatin for cisplatin, yet this is done regularly in the United States, especially in the elderly. The largest clinical trial experience and only randomized data with this approach are from the CALGB-9633 trial, which included 344 stage IB patients. The final analysis of the trial was negative with an OS HR of 0.83 (90% CI, 0.64–1.08; P = .125), although it was more of a benefit in patients with larger tumors as mentioned above. In practice, carboplatin use in the adjuvant setting should be reserved for patients who are unable to tolerate cisplatin.

Besides adjuvant cisplatin-based doublet chemotherapy, substantial evidence supports other strategies such as with oral chemotherapeutics. In Asia, particularly Japan, the combination of uracil and tegafur (a prodrug of 5-fluorouricil) has been studied extensively and is used for stage I tumors based on an OS benefit in stage I patients with tumors greater than 2 cm in size. The ongoing JCOG-0707 trial is comparing uracil/tegafur with S-1, an oral agent composed of tegafur and gimeracil.

Elderly patients

Certain subsets of patients deserve mention, particularly the elderly. About a third of patients enrolled on JBR.10 were 65 years or older, and this subgroup had a significant OS benefit from adjuvant chemotherapy (HR, 0.61; 95% CI, 0.38–0.98; P = .04). In a broader evaluation of all trials included in the LACE meta-analysis, the 414 patients (9%) who were at least 70 years old had no increase in severe toxicity rates but only a trend toward a survival benefit with adjuvant chemotherapy (HR, 0.90; 95% CI, 0.70–1.16; P = .29). A Canadian analysis of population-based data from the Ontario cancer registry identified a significant increase in use of adjuvant chemotherapy in the elderly after 2004 to 2006, with a resultant increase in 4-year survival. Of note, 70% of the elderly who received adjuvant chemotherapy in that analysis received cisplatin.

Neoadjuvant chemotherapy

The data in support of neoadjuvant chemotherapy are more limited, partially because larger trials examining neoadjuvant therapy were halted early when the positive adjuvant trial results were known and surgery alone control arms were no longer thought to be appropriate. One of the largest studies, Chemotherapy for Early Stages Trial, randomly assigned 270 patients with stages IB, II, and IIIA NSCLC to 3 cycles of induction chemotherapy with cisplatin and gemcitabine followed by surgery versus surgery alone. Both DFS (HR, 0.70; P = .003) and OS (HR, 0.63; P = .02) were significantly in favor of the chemotherapy arm, although this benefit was limited to those patients with stage IIB/IIIA disease. The largest trial (N = 624) to directly compare neoadjuvant with adjuvant with no chemotherapy for resected early-stage lung cancer was restricted to stage IA (at least 2 cm in size), IB, II, and T3N1 disease. The Neo-adjuvant versus Adjuvant Taxol/Carbo Hope (NATCH) trial used carboplatin/paclitaxel chemotherapy and included a high percentage of stage I patients, which may explain why no significant differences were found between the 3 arms, although 5-year DFS rates favored the chemotherapy arms. Therefore, a look at the meta-analyses may provide a better understanding of neoadjuvant chemotherapy. An analysis of 590 patients from 6 randomized trials published from 1990 to 2003 concluded that neoadjuvant chemotherapy led to a nonsignificant improvement in OS (HR 0.65, 95% CI, 0.41–1.04). In 2010 a meta-analysis of 13 randomized trials reported an OS HR of 0.84 (95% CI, 0.77–0.92; P = .0001) in favor of the neoadjuvant chemotherapy. The largest meta-analyses based on individual patient data are from 15 randomized studies of neoadjuvant chemotherapy (N = 2385) and reported an OS HR of 0.87 (95% CI, 0.78–0.96; P = .007), corresponding to a 5% absolute survival benefit at 5 years in keeping with what is seen in the adjuvant trial meta-analyses.

Chemotherapy biomarkers

The discovery of appropriate biomarkers for selection of patients for adjuvant chemotherapy has been challenging. Numerous prognostic gene signatures have been reported, with 1 predictive marker developed in the JBR.10 trial but not used in practice. The DNA repair enzyme ERCC1 was thought to be a biomarker of cisplatin benefit on IALT, but subsequent work refuted those findings and led to closure of the French intergroup TASTE trial designed on ERCC1 testing. The Spanish Lung Cancer Group also attempted to better select chemotherapy based on analysis of enzymes involved in DNA repair but also failed to show a benefit with this approach. The Italian ITACA trial results are awaited as the last trial investigating this approach to chemotherapy selection.

Molecularly targeted therapy

With the rapid increase in our knowledge about molecular drivers of NSCLC and the benefits of targeted treatment in advanced disease, the logical extension was to study the targeted agents in earlier stages of lung cancer to attempt an increase in cure rates. The most extensive experience is the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Compared with first-line chemotherapy treatment, patients with advanced-stage NSCLC harboring EGFR mutations have higher response and longer progression-free survival (PFS) when treated with EGFR-targeted TKIs with randomized phase III data in that setting with gefitinib, erlotinib, and afatinib. In multiple trials for metastatic NSCLC with activating mutations in EGFR, the EGFR TKIs produce superior response and PFS compared with platinum doublet chemotherapy in treatment naïve patients. Other than in subset analysis, however, an OS benefit has not been demonstrated, likely because of crossover. The lack of a survival benefit is an issue in the adjuvant setting, where cure is the goal. Similar outcomes with significant response and PFS improvements with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib compared with chemotherapy have been reported in patients with tumors harboring translocations of ALK.

The idea of using targeted TKI therapy in the adjuvant therapy is not unique to lung cancer. For patients with resected early-stage HER2-positive breast cancer, the use of the HER2 antibody trastuzumab for 1 year improves OS, and the use of adjuvant imatinib for patients with resected gastrointestinal stromal tumor is an established standard after trials proved this approach improves OS. Results with targeted adjuvant therapy in early-stage lung cancer, however, have been more complicated.

The earliest data for adjuvant TKI therapy in resected lung cancer were retrospective analyses and nonrandomized studies. A retrospective Chinese study identified 138 patients with completely resected early-stage adenocarcinoma with EGFR-mutated disease and showed no differences in recurrence risk or survival compared with a matched cohort that differed in EGFR mutation status. The investigators also looked at the 31 patients with EGFR-mutant lung cancer who received EGFR TKI therapy compared with the 107 who did not. Those who received adjuvant EGFR TKIs had longer DFS than those who did not ( P = .033) but no median OS difference ( P = .258). Nevertheless, there was a longer 3-year OS in those receiving EGFR TKI (92.5% vs 81%). Another large retrospective cohort of patients from Memorial Sloan Kettering Cancer Center with completely resected early stage (I–III) EGFR-mutant lung adenocarcinoma were evaluated for outcomes based on whether they received adjuvant EGFR TKI therapy. This was a nonrandomized approach in which approximately one-third of evaluated patients (n = 56) received perioperative EGFR TKI therapy. In a multivariate analysis controlling for known prognostic factors (sex, stage, type of surgery, and adjuvant platinum chemotherapy), the authors reported a 2-year DFS of 89% for patients treated with adjuvant TKI compared with 72% in those not treated with an adjuvant TKI (HR, 0.53; 95% CI, 0.28–1.03; P = .06). The OS HR was 0.62 (95% CI, 0.26–1.51; P = .296).

The largest nonrandomized prospective study, the SELECT study, investigated adjuvant erlotinib in resected early-stage (IA–IIIA) EGFR mutation–positive NSCLC patients. The 100 enrolled patients received erlotinib 150 mg daily for 2 years after completion of optional adjuvant chemotherapy, and with a median follow-up of 3 years, the 2-year DFS was 90% (97% stage I, 73% stage II, and 92% stage III).

These encouraging data led to randomized trials, although many were initiated before the importance of EGFR mutations in selection of therapy was well established. NCIC CTG BR19 was a randomized, double-blind, placebo-controlled trial of 2 years of adjuvant gefitinib or placebo for completely resected NSCLC. Because the patients were not selected for EGFR mutations, the subset with EGFR mutations was very small (n = 15), with no clear benefit of gefitinib shown. The larger phase III, randomized RADIANT trial looked at adjuvant erlotinib for resected early-stage NSCLC patients (who could have received prior adjuvant chemotherapy) selected for EGFR expression by immunohistochemistry and fluorescence in situ hybridization but not by EGFR mutation status. The study was powered for a primary endpoint of DFS in the full data set, with secondary analyses including DFS and OS in patients with del19 or L858R EGFR activating mutations. Nearly 1000 patients were enrolled, and no statistically significant differences were found in DFS or OS in the overall group. For the subset of 161 patients with activating EGFR mutations, however, the DFS did favor erlotinib (HR, 0.61; 95% CI, 0.384–0.981; P = .0391). The study was designed such that no endpoint would be considered statistically significant if the primary endpoint was negative; thus, the EGFR mutation subset results are not statistically significant. Of further concern, at the time of publication, the OS results, although not mature, did not favor the erlotinib arm in the EGFR mutation–positive subset. Thus, the use of adjuvant EGFR TKI therapy should still be restricted to clinical trial use. Multiple trials are ongoing in North America and Asia further exploring this option and looking at the use of adjuvant ALK inhibitors in patients with resected early-stage ALK-positive NSCLC ( Table 1 ).

Table 1

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