Optimal adjuvant therapy for non-small cell lung cancer--how to handle stage I disease

The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.     

ⅠB期非小细胞肺癌术后辅助化疗的争议和共识

临床上有20％～25％的非小细胞肺癌（NSCLC）患者可手术治疗,但5年生存率也只有40％左右。辅助化疗是部分早期可切除肺癌的标准治疗方式,可使4％～15％的患者生存获益。但是,ⅠB期NSCLC是否能从辅助化疗中获益仍存在争议。近年来,多个临床研究评价了ⅠB期NSCLC辅助化疗的疗效,我们通过分析这些临床研究,寻找ⅠB期NSCLC的高危人群和辅助化疗的适应证。     

Chemotherapy in stage I+II non-small cell lung cancer

Although surgical resection offers the best chance for long-term survival for patients with non-small cell lung cancer (NSCLC), the limited number of resectable patients and the presence of micrometastatic disease is limiting the effectiveness of this modality as sole treatment. Results of randomized trials demonstrated a survival benefit for preoperative (neoadjuvant) cisplatin-based chemotherapy in patients with stage IIIA NSCLC compared to surgery alone. In stage I+II NSCLC preoperative chemotherapy, although still experimental, clearly offers encouraging results. However, there is no evidence of its superiority over adjuvant chemotherapy. Moreover, for adjuvant therapy a benefit has not been established yet. Possibly current ongoing or recently finished trials may change the recommendations on adjuvant or neoadjuvant therapy for completely resected or resectable early disease in the future.     

Prognostic factors for survival of stage I nonsmall cell lung cancer patients : a population-based analysis of 19,702 stage I patients in the California Cancer Registry from 1989 to 2003

BACKGROUND: Platinum-based adjuvant chemotherapy in randomized trials has failed to provide a survival benefit in patients with resected stage I nonsmall cell lung cancer (NSCLC). Using data from the California Cancer Registry (CCR), we explored factors that had detrimental effects on survival in patients with stage I NSCLC to identify a subset of patients at high risk for disease recurrence and subsequent mortality. METHODS: Between 1989 and 2003, 19,702 incident cases of stage I NSCLC in the CCR were identified and subgrouped into stage IA and IB disease. Patient demographic factors, tumor characteristics, and treatment delivered were examined. Kaplan-Meier survival curves were calculated to estimate survival rates. Cox proportional-hazards ratios were used to identify independent prognostic factors for survival. RESULTS: Advanced age at diagnosis, male sex, low socioeconomic status (SES), nonsurgical treatment, and poor histologic grade (stage IA NSCLC: hazards ratio [HR], 1.13; 95% confidence interval [95% CI], 1.08-1.19; stage IB NSCLC: HR, 1.11; 95% CI, 1.07-1.16) were associated with increased mortality risk on multivariate analysis. Non-upper lobe tumor location (right middle lobe, right and left lower lobes) and tumor size > or =4 cm (vs <4 cm: HR, 1.23; 95% CI, 1.15-1.30) were additional factors that increased the risk of mortality among patients with stage IB disease. Bronchioloalveolar carcinoma and Asian ethnicity were associated with decreased mortality risk in stage I NSCLC. CONCLUSIONS: Stage I NSCLC with poorly differentiated histology and stage IB NSCLC with non-upper lobar tumor location or tumor size > or =4 cm carried an increased mortality risk.     

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.     

The role of chemotherapy in early-stage (stage I and II) resectable non-small cell lung cancer

For patients with stage I or II non-small cell lung cancer (NSCLC), surgical resection is considered the standard of care. Although surgery achieves long-term survival in many patients, a significant proportion experience locoregional or distant recurrence. Five-year survival rates after resection for stage I and II NSCLC range from 38% (T3 N0) to 67% (T1 N0). Efforts at improving survival for early-stage NSCLC patients have focused on the use of chemotherapy administered postoperatively (adjuvant) or preoperatively (neoadjuvant or induction) to eradicate micrometastatic disease. The majority of trials examining adjuvant chemotherapy have not found a survival benefit. A meta-analysis examining the role of chemotherapy in the treatment of NSCLC found a 5% absolute improvement in 5-year survival associated with the use of adjuvant cisplatin-based chemotherapy (P =.08). Chemotherapy administered before surgery or definitive irradiation has improved survival rates in patients with stage III NSCLC. The role of induction chemotherapy in stage I and II NSCLC is currently under investigation.     

Adjuvant and neoadjuvant chemotherapy in NSCLC: a paradigm shift

The role of adjuvant chemotherapy in patients with early-stage non-small cell lung cancer (NSCLC) remained controversial for many years. Although a positive impact on overall survival was long suggested for cisplatin-based chemotherapy, early randomized clinical trials failed to confirm a clear survival benefit. Recently, the results from 4 large randomized trials, IALT, JBR.10, CALGB 9633, and ANITA indicate a significant survival benefit with adjuvant chemotherapy for patients with IB through IIIA NSCLC, and the results of these trials support the adoption of chemotherapy in addition to surgery as a new standard of care. Neoadjuvant chemotherapy is potentially better tolerated compared to post-surgical adjuvant chemotherapy, though definitive survival benefits with this approach have yet to be shown. The current status of adjuvant and neoadjuvant chemotherapy for patients with early-stage NSCLC will be discussed.     

Postoperative Chemotherapy Use and Outcomes From ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR-Mutated NSCLC

IntroductionAdjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA.MethodsPatients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB–IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage.ResultsOverall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10–0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13–0.40), regardless of disease stage.ConclusionsThese findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy.     

Current development of adjuvant treatment of non-small-cell lung cancer

Although radical surgery remains the mainstay therapeutic modality for early-stage non-small-cell lung cancer (NSCLC), long-term survival of patients with completely resected NSCLC tumors remains suboptimal. Globally, the 5-year survival rate of patients who undergo complete surgical resection is in the range of 40%-50%. The majority of postsurgical relapses are represented by distant metastases, with the risk of a local recurrence being < 10%. Postoperative treatments, including chemotherapy, radiation therapy, or both, have been widely evaluated during recent decades. After almost 2 decades of disappointing results, the positive outcomes of 3 randomized studies have recently generated new hopes for a significant impact on survival by adjuvant chemotherapy. The 2 largest randomized studies of adjuvant chemotherapy in all stages (I-IIIA) of completely resected NSCLC that were adequately powered to detect small differences in survival yielded partially conflicting results but indicated that, if any benefit from adjuvant chemotherapy exists, it is approximately 5% at 5 years, as previously anticipated by a metaanalysis. More recently, 2 other randomized studies in selected subgroups of patients (one selectively performed in stage IB disease, the other in stage IB/II disease) indicate an unexpected significant benefit of approximately 15% at 5 years. Potential confounding factors may have contributed to such a significant benefit. A feature common to all these trials is the suboptimal therapeutic compliance to adjuvant chemotherapy, suggesting the need for careful selection of patients to be considered for adjuvant treatment. Genomic- and proteomic-driven chemotherapy as well as molecularly targeted therapies may represent additional areas of near-future clinical investigations.     

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.     

The role of surgery in stage IIIA non-small cell lung cancer

For most patients who have stage III non-small cell lung cancer (NSCLC), a combination of chemotherapy and radiation represents the current treatment of choice. Recent developments include the use of adjuvant chemotherapy after up-front surgery in subgroups of patients who have stage III disease, as well as innovative ways to deliver concurrent chemoradiotherapy or combinations of chemotherapy with higher-dose conformal radiotherapy techniques. This article focuses on patients who have stage IIIA NSCLC and reviews the different possibilities for their treatment. Special emphasis is given to the inclusion of surgery into the different approaches to this disease stage. The current literature on this topic is reviewed, and the different aspects of surgical treatment in the management of stage IIIA NSCLC are discussed.     

Adjuvant and neoadjuvant therapy for early-stage non-small-cell lung cancer

Early-stage non-small-cell lung cancer (NSCLC) carries with it an unfavorable prognosis even in patients who have undergone surgical intervention. Efforts to improve the outcome of patients with early-stage NSCLC have focused on adjuvant or neoadjuvant chemotherapy. The role of adjuvant therapy in NSCLC has been clarified by the recent publication of several large randomized trials. The International Adjuvant Lung Trial was the first prospective trial to report that adjuvant chemotherapy following complete surgical resection of NSCLC improved absolute overall survival by approximately 5% at 5 years. This result has subsequently been confirmed by several other trials. As a result, adjuvant chemotherapy following complete resection of stage IB-III NSCLC can now be considered the standard of care. Neoadjuvant chemotherapy, which has long been investigated for stage III NSCLC, was also recently explored in stage I/II NSCLC. Although neoadjuvant chemotherapy seems promising, more work is needed to comprehensively evaluate and optimize this approach. The current evidence for adjuvant and neoadjuvant therapy in early-stage NSCLC is reviewed in this article.     

Neoadjuvant chemotherapy in stage III NSCLC

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related mortality in the United States. Current standard care for treating NSCLC is surgical resection, when feasible, followed by adjuvant chemotherapy in stages II and III. Neoadjuvant or induction chemotherapy may have several potential advantages compared with adjuvant chemotherapy and has been evaluated in randomized and nonrandomized clinical trials in NSCLC. This article reviews the data for neoadjuvant chemotherapy in NSCLC with a particular focus on regionally advanced disease (stage III) that is still amenable to surgical resection.     

Adjuvant chemotherapy in elderly patients with non-small-cell lung cancer.

BACKGROUND: More than two thirds of patients who die of lung cancer in the United States are over 65 years of age. More than 50% of lung cancer patients are diagnosed over the age of 65 and about 30% over the age of 70. METHODS: The authors review recent data from large randomized trials on adjuvant chemotherapy in patients with NSCLC. They discuss age-related changes in organ function, comorbidities and frailty in the elderly, and chemotherapy treatment in elderly patients with NSCLC. RESULTS: Randomized trials suggest that postoperative chemotherapy improves survival after surgery in patients with stage IB to IIIA NSCLC, and awareness of the efficacy of this approach is growing in the scientific community. Clinical data obtained in the young population cannot be automatically adopted in the elderly counterpart. Elderly patients tolerate chemotherapy poorly because of comorbidity and organ failure, and after lung surgery they are considered at higher risk of chemotherapy-induced toxicity. The survival benefit obtained with platin-based chemotherapy may vanish or decrease in the elderly due to a potential higher toxic death rate or lower compliance to treatment. CONCLUSIONS: Modified schedules or attenuated dose of platin-containing chemotherapy should be investigated in the adjuvant setting by specifically designed trials. Specifically designed prospective trials are needed to elucidate the role of this approach in the elderly.     

Uptake and tolerance of adjuvant chemotherapy in early stage NSCLC patients in Alberta, Canada

Adjuvant chemotherapy for early stage non-small cell lung cancer was approved for provincial insurance coverage in Alberta, Canada in 2004. The purpose of this study was to measure factors related to uptake of chemotherapy in eligible patients and compare toxicity and survival outcomes in the Alberta population with those found in clinical trials. All Alberta residents diagnosed with stage IB-IIB NSCLC from 2004 to 2006 who had surgery and a consultation with an oncologist to discuss initial treatment were included in the study. Diagnostic, demographic, and vital statistics data were obtained from the Alberta Cancer Registry; chart reviews were conducted to identify details related to treatments discussed, refused, co-morbidities, and toxicity. Analyses were conducted to identify factors associated with discussion and receipt of chemotherapy and toxicity. Toxicity and survival were calculated and compared to clinical trial results. 226 patients were included in the study. Adjuvant chemotherapy was not recommended to 57 patients (25%) and 30 patients (13%) refused chemotherapy. Primary reasons for not recommending chemotherapy were co-morbidities and/or frailty (24 patients). Of the 139 patients who began chemotherapy, 47 (34%) stopped treatment early. Stage II patients who received adjuvant chemotherapy had over a 2-fold decrease in risk of death compared to those who did not receive chemotherapy after adjusting for age and co-morbidities. Efforts to improve uptake of adjuvant chemotherapy in patients with stage II NSCLC should be made as the survival advantage appears to be comparable to that found in clinical trials.     

Adjuvant chemotherapy for non-small cell lung cancer

Recently, several randomized trials with a large number of enrolled patients have shown that postoperative adjuvant treatment improves survival among patients with completely resected non-small cell lung cancer (NSCLC). Platinum-based chemotherapy has been reported to be effective for patients with postoperative stage I to IIIA NSCLC in western countries. On the other hand, uracil-tegafur was also shown to improve survival among patients with stage I adenocarcinoma in Japan. We reviewed the results of recent randomized trials and meta-analyses, and discuss the current role and problems related to adjuvant chemotherapy in NSCLC.     

Consensus development conference on the medical treatment of non-small cell lung cancer: treatment of the early stages

Surgery remains the mainstay of treatment for early non-small cell lung cancer (NSCLC) but more than 80% of recurrences occur within 2 years from radical surgery. The pattern of recurrence may differ by histology with more local recurrences seen for patients with squamous cell carcinoma and more distant metastases seen in patients with adenocarcinoma. A number of studies demonstrate that dissemination of cancer cells at levels much below those detected by any current available imaging techniques, including PET scanning also, affect prognosis of patients with clinical early-stage NSCLC. The current clinical evidence does not recommend adjuvant chemotherapy and/or radiotherapy in completely resected stage I-II-IIIA for N1. There are few randomised trials available for analysis of neo-adjuvant chemotherapy involving patients with resectable stage III disease; overall these trials suggest that induction chemotherapy (with or without radiation) improves survival, particularly in those patients who undergo significant downstaging. Heterogeneous study populations limit the ability to define the optimal patient population who would most benefit from this approach. There is no conclusive evidence that neo-adjuvant chemotherapy in early NSCLC is associated with an increased post surgical morbility and mortality. Additional trials are needed. More recently neo-adjuvant chemotherapy has been tested in resectable stage I-II NSCLC and proved to be feasible and better tolerated than adjuvant chemotherapy. Several randomised trials are currently ongoing. In the next future the role of targeted biological therapies as agents acting on minimal residual disease should be explored.     

Treatment of stage IB2 (bulky) cervical carcinoma

Tumour size is an important prognostic factor in patients with stage IB cervical cancer. The patient with stage IB2 (bulky) cervical cancer represents a therapeutic challenge. Neither radical hysterectomy nor primary radiation therapy are sufficiently effective and are associated with significant treatment-related complications including ovarian failure and psychosexual deficits. A number of phase III studies have explored alternative management approaches in this patient population. It appears that extrafascial hysterectomy following radiation therapy does not improve overall survival relative to radiation therapy alone. Consistent with results seen in locally advanced cervical carcinoma, chemoradiation therapy is superior to radiation therapy alone as primary treatment for stage IB2 cervical cancer and as adjuvant therapy for surgically treated patients with high-risk factors for recurrence. Neoadjuvant chemotherapy has resulted in high clinical response rates and operability rates. There are two phase III trials suggesting an improvement in survival with neoadjuvant chemotherapy followed by radical hysterectomy versus either surgery (and selected postoperative radiation) or radiation therapy alone. These emerging treatments should be scrutinized in prospective controlled trials.     

Pre-operative chemotherapy in early stage resectable non-small-cell lung cancer: a randomized feasibility study justifying a multicentre phase III trial

Surgical resection offers the best chance for cure for early stage non-small-cell lung cancer (NSCLC, stage I, II, IIIA), but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage (IB, II, IIIA) resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m(-2), vinblastine 6 mg m(-2) and cisplatin 50 mg m(-2) (MVP)] followed by surgery (n = 11), or to surgery alone. Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III-IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial.     

Controversies in the management of stage IIIA non-small-cell lung cancer

New developments in the management of non-small-cell lung cancer, as well as recent proposals for changing the current lung cancer staging system, are posing a challenge in the therapeutic decision making regarding this disease. For the last two decades, the management of stage IIIA (N2) disease has been controversial and the target for clinical trials has been to determine the best therapeutic approach that may result in better survival outcomes without increasing toxicity. For many years, combined modality treatment (systemic chemotherapy plus radiation therapy) became the standard of care in this setting. However, the poor outcomes seen with combined modality for N2 has obligated us to explore other possibilities. In this sense, recent clinical trials in the neoadjuvant setting using chemotherapy alone or combined modality are providing fruitful results and shifting the paradigm on this stage. A recent, large randomized multicenter trial argues against what has slowly become a current practice in some centers – the use of preoperative modality for N2 disease. Another controversy that we will discuss here is the acceptance of adjuvant therapy for resected stage IB–IIIA non-small-cell lung cancer. It was not long ago that adjuvant radiation therapy was still the standard of care for patients who have pathological nodal disease. We will present the current data on these debatable issues and how to implement this new knowledge into clinical practice.