Adjuvant Therapy in Non‐Small Cell Lung Cancer: Current and Future Directions

The cornerstone of treatment for early‐stage non‐small cell lung cancer (NSCLC) has long been surgical resection. Over the past few years, there has been a paradigm shift to provide adjuvant platinum‐based chemotherapy for patients with completely resected stage II–IIIA NSCLC founded on large randomized clinical trials demonstrating longer overall survival with this treatment. Reassuringly, the National Cancer Institute of Canada Cancer Therapeutics Group JBR.10 trial recently reported a continued survival advantage for patients treated with adjuvant chemotherapy after >9 years of median follow‐up. In contrast, the gains from using this approach for stage IB disease are less clear, although data from an unplanned subgroup analysis suggest benefit for patients with tumors ≥4 cm. Herein, we review the evidence supporting adjuvant therapy in early‐stage NSCLC patients before discussing key mitigating factors in providing treatment, such as stage of disease and the impact of the new seventh edition of the tumor–node–metastasis classification system. Criteria such as patient age and performance status, as well as the value of appropriate chemotherapy selection, are highlighted as measures to help guide management. The role of postoperative radiotherapy and the future landscape of early‐stage NSCLC research are also explored; namely, therapeutic strategies exploiting pharmacogenomic and gene‐expression profiling, in an attempt to personalize care, and the integration of novel targeted therapies into adjuvant clinical trials.     

Cost‐Effectiveness of a 14‐Gene Risk Score Assay to Target Adjuvant Chemotherapy in Early Stage Non‐Squamous Non‐Small Cell Lung Cancer

Purpose.

Life Technologies has developed a 14-gene molecular assay that provides information about the risk of death in early stage non-squamous non-small cell lung cancer patients after surgery. The assay can be used to identify patients at highest risk of mortality, informing subsequent treatments. The objective of this study was to evaluate the cost-effectiveness of this novel assay.

Patients and Methods.

We developed a Markov model to estimate life expectancy, quality-adjusted life years (QALYs), and costs for testing versus standard care. Risk-group classification was based on assay-validation studies, and chemotherapy uptake was based on pre- and post-testing recommendations from a study of 58 physicians. We evaluated three chemotherapy-benefit scenarios: moderately predictive (base case), nonpredictive (i.e., the same benefit for each risk group), and strongly predictive. We calculated the incremental cost-effectiveness ratio (ICER) and performed one-way and probabilistic sensitivity analyses.

Results.

In the base case, testing and standard-care strategies resulted in 6.81 and 6.66 life years, 3.76 and 3.68 QALYs, and $122,400 and $118,800 in costs, respectively. The ICER was $23,200 per QALY (stage I: $29,200 per QALY; stage II: $12,200 per QALY). The ICER ranged from “dominant” to $92,100 per QALY in the strongly predictive and nonpredictive scenarios. The model was most sensitive to the proportion of high-risk patients receiving chemotherapy and the high-risk hazard ratio. The 14-gene risk score assay strategy was cost-effective in 68% of simulations.

Conclusion.

Our results suggest that the 14-gene risk score assay may be a cost-effective alternative to standard guideline-based adjuvant chemotherapy decision making in early stage non-small cell lung cancer.     

Cost‐Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early‐Stage Non‐Small Cell Lung Cancer

Background.

A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC.

Materials and Methods.

Lifetime costs (2014 U.S. dollars) and effectiveness (quality-adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty.

Results.

Lifetime costs and effectiveness were $137,403 and 5.45 QALYs with the prognostic test and $127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was $35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of $50,000/QALY.

Conclusion.

The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost-effective compared with using the SoC based on globally accepted willingness-to-pay thresholds.

Implications for Practice:

Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests.     

The Rationale for Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer

The past decade has witnessed renewed interest in studies exploring the benefits of adjuvant (postoperative) chemotherapy (± radiation therapy) in patients with resected non-small cell lung cancer (NSCLC). Recently completed adjuvant trials have included a heterogeneous group of patients with resected stages I to IIIA NSCLC. With rare exception, the published results of these studies indicate adjuvant chemotherapy imparts a significant overall survival advantage. Subset analyses suggest survival benefit occurs primarily in patients with resected stage II or IIIA and is less likely to occur in stage I patients. This apparent lack of survival benefit in stage I patients was seemingly validated in a prospective trial conducted by the Cancer and Leukemia Group B in which stage IB patients were randomized to observation or adjuvant carboplatin and paclitaxel. Survival at 5 -years was identical in the two arms of this trial. By contrast, two contemporary postoperative chemotherapy trials also conducted exclusively in stage I NSCLC patients yielded positive survival results. The divergent outcome of the prospective trials along with the negative subset analyses has created uncertainty as to the utility of postoperative adjuvant chemotherapy in stage I NSCLC. Herein we review the data underlying this controversy and offer a proposed algorithm to aid the clinician in selecting patients whom we believe may benefit from adjuvant chemotherapy. The treatment algorithm is based on currently available tumor- and host-related factors that affect prognosis.     

经倾向指数匹配后手术切除合并辅助化疗和非手术治疗局限期小细胞肺癌的疗效比较

目的：应用倾向指数匹配法均衡组间协变量,评价手术切除合并辅助化疗对治疗局限期小细胞肺癌的疗效。方法：回顾性分析了本院2009年至2014年间诊断为局限期小细胞肺癌的157例住院患者临床资料。其中61例接受手术切除合并辅助化疗,96例接受单纯化疗或放化疗联合治疗。利用倾向指数评分方法,匹配卡钳值0.20,以治疗方式为因变量,以T分期,N分期,病灶数量和病理分型为协变量,均衡不平衡的协变量,模拟出随机化效果。分别对匹配前后的数据进行生存分析。结果：匹配前,手术组和非手术组的中位生存期分别为27个月（95%CI,2.73-51.26）和14个月（95%CI,11.8-16.18）。匹配后,所有协变量分布均达到均衡。比较匹配后两组患者的生存状况,手术组患者的中位生存期为27个月,非手术组中位生存期为17个月(95%CI,13.68-20.32)。Log-rank检验两组生存率具有统计学差异,P=0.001。结论：对于局限期小细胞肺癌患者,如果达到手术切除的临床指证,手术切除合并辅助化疗能使患者的生存获益。在治疗前如能准确诊断为小细胞肺癌的患者,临床分期能指导选择合适的治疗策略。     

Adjuvant Chemotherapy Following Surgical Resection Improves Survival in Patients With Early Stage Small Cell Lung Cancer

The purpose of this study was to determine the effects of resection coupled with standard chemotherapy on the survival prognosis of patients with early stage small cell lung carcinoma (SCLC). Patients (n=110) with mediastinal lymph node-negative SCLC were enrolled in this study. The baseline clinical data of patients with surgery were retrospectively reviewed. Overall survival (OS) and progression-free survival (PFS) were measured by Kaplan–Meier and log-rank test analyses. Ninety-eight patients received mediastinoscopy biopsy, and pulmonary lobectomy or sublobar resection, and 67 patients underwent adjuvant chemotherapy after pulmonary lobectomy. Adjuvant chemotherapy after surgical intervention was associated with longer OS (median OS: 42.14 vs. 33.53 months, p=0.01) and PFS (median PFS: 25.20 vs. 13.48 months, p=0.000) compared to resection alone for all patients. Adjuvant chemotherapy was associated with improvement of survival for N1 patients with stage II (median OS: 36.42 vs. 26.68 months, p=0.021). The median PFS was 19.02 m (16.08, 21.96) and 13.25 m (10.19, 16.30) (p=0.031), respectively, for patients of N1 stage who received chemotherapy and those who did not. Cox regression analysis demonstrated that age, TNM stage (N stage, not T stage), and chemotherapy were independent risk factors that might affect overall survival in patients with mediastinal lymph node-negative SCLC. These findings suggest that the application of adjuvant chemotherapy following pulmonary lobectomy is associated with improvements of survival prognoses for patients with SCLC. The combination of surgical intervention with conventional therapy should be taken into consideration as a prospective multidisciplinary regimen for early stage SCLC.     

Measuring the Population Impact of Introducing Stereotactic Ablative Radiotherapy for Stage I Non‐Small Cell Lung Cancer in Canada

Background.

The Cancer Risk Management Model (CRMM) was used to estimate the health and economic impact of introducing stereotactic ablative radiotherapy (SABR) for stage I non-small cell lung cancer (NSCLC) in Canada.

Methods.

The CRMM uses Monte Carlo microsimulation representative of all Canadians. Lung cancer outputs were previously validated internally (Statistics Canada) and externally (Canadian Cancer Registry). We updated costs using the Ontario schedule of fees and benefits or the consumer price index to calculate 2013 Canadian dollars, discounted at a 3% rate. The reference model assumed that for stage I NSCLC, 75% of patients undergo surgery (lobectomy, sublobar resection, or pneumonectomy), 12.5% undergo radiotherapy (RT), and 12.5% undergo best supportive care (BSC). SABR was introduced in 2008 as an alternative to sublobar resection, RT, and BSC at rates reflective of the literature. Incremental cost effectiveness ratios (ICERs) were calculated; a willingness-to-pay threshold of $100,000 (all amounts are in Canadian dollars) per quality-adjusted life-year (QALY) was used from the health care payer perspective.

Results.

The total cost for 25,085 new cases of lung cancer in 2013 was calculated to be $608,002,599. Mean upfront costs for the 4,318 stage I cases were $7,646.98 for RT, $8,815.55 for SABR, $12,161.17 for sublobar resection, $16,266.12 for lobectomy, $22,940.59 for pneumonectomy, and $14,582.87 for BSC. SABR dominated (higher QALY, lower cost) RT, sublobar resection, and BSC. RT had lower initial costs than SABR that were offset by subsequent costs associated with recurrence. Lobectomy was cost effective when compared with SABR, with an ICER of $55,909.06.

Conclusion.

The use of SABR for NSCLC in Canada is projected to result in significant cost savings and survival gains.     

A Prospective Study of Shortened Vitamin Supplementation Prior to Cisplatin–Pemetrexed Therapy for Non‐Small Cell Lung Cancer

Background.

Prior supplementation with folic acid and vitamin B₁₂ is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen.

Methods.

Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B₁₂ by intramuscular injection and began taking 350–500 μg of oral folic acid daily. Starting 24–48 hours after the vitamin B₁₂ injection, the patients received intravenous 500 mg/m² pemetrexed and 75 mg/m² cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3.

Results.

Thirty patients received chemotherapy starting within 48 hours of the vitamin B₁₂ injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%.

Conclusion.

The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.