Adjuvant therapy of resected non-small-cell lung cancer

Surgical resection of early-stage non-small-cell lung cancer (NSCLC) remains the standard of care in patients fit for surgery. Careful preoperative staging is imperative, as is pathologic documentation of the mediastinal nodal contents. Adjuvant postoperative thoracic radiation therapy (RT) clearly has an impact in reducing locoregional recurrence but has no clear impact on survival. The Postoperative RT (PORT) metaanalysis raised concerns about PORT, particularly in stage I/II NSCLC, suggesting it may negatively impact survival. This was not a concern in stage III NSCLC, in which the risk of locoregional recurrence is higher. However, distant recurrence remains the dominant pattern in resected NSCLC, suggesting that the majority of patients with early-stage resected NSCLC harbor occult micrometastatic disease. Historically, the role of adjuvant chemotherapy has been controversial, and its routine use was not supported by the published data, which consisted of a small number of underpowered trials using inadequately delivered, antiquated chemotherapy. More recently, larger trials have been reported with conflicting results. Like adjuvant PORT, chemotherapy combined with RT has not improved survival over PORT alone. The use of adjuvant cisplatin-based therapy did not show a survival advantage in the Adjuvant Lung Project Italy study but did in the International Adjuvant Lung Trial, creating controversy in the routine implementation of adjuvant therapy in all patients. Recently completed randomized trials by the Cancer and Leukemia Group B and the National Cancer Institute of Canada provide convincing evidence of a substantial benefit from adjuvant therapy in well-staged and completely resected stage I/II NSCLC. Currently, the totality of the data supports a discussion with patients with resected NSCLC regarding the potential benefits of adjuvant therapy.     

Current status of adjuvant chemotherapy for stage IB non-small-cell lung cancer: implications for the New Intergroup Trial

Adjuvant chemotherapy after resection of stage II-IIIA non-small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non-small-cell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (>or= 4 cm) and will likely include only cisplatin-based regimens.     

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.     

Current Status of Adjuvant Chemotherapy for Stage IB Non–Small-Cell Lung Cancer: Implications for the New Intergroup Trial

Adjuvant chemotherapy after resection of stage II-IIIA non–small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non–smallcell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (≥ 4 cm) and will likely include only cisplatin-based regimens.     

Highlights from the Tenth World Conference on Lung Cancer

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.     

Postoperative Adjuvant Systemic Therapy in Completely Resected Non–Small-Cell Lung Cancer: A Systematic Review

The purpose of the present review was to determine whether the use of postoperative adjuvant systemic therapy in patients with completely resected non–small-cell lung cancer (NSCLC) improves survival. Cancer Care Ontario's Program in Evidence-Based Care reviewed the evidence to update previously published recommendations for patients with completely resected NSCLC. Relevant studies were identified from a systematic MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews search of studies published from 2010 to 2016. All phase III randomized controlled trials (RCTs) and relevant systematic reviews were included. Data on overall survival (OS), disease-free survival, adverse events, and quality of life were extracted from each of the studies. Two relevant systematic reviews, 13 RCTs, and a series of pooled analyses by Lung Adjuvant Cisplatin Evaluation-Biomarker were included in the present review. Adjuvant chemotherapy statistically significantly improved OS for resected stage II-IIIA NSCLC and is recommended. For patients with stage IB NSCLC, no significant improvement was seen in OS; however, the results from subgroup analyses indicate that it would be reasonable to consider adjuvant chemotherapy for patients with larger tumors (≥ 4 cm). The present data do not support the use of adjuvant novel therapies (ie, epidermal growth factor receptor tyrosine kinase inhibitor, bevacizumab, and immunotherapy) either as an addition to, or instead of, cytotoxic chemotherapy. No predictive biomarkers are available to select patients more likely to benefit from adjuvant chemotherapy. Cytotoxic chemotherapy remains the standard of care as adjuvant therapy for patients with resected stage II-IIIA NSCLC. Additional clinical trials are needed to evaluate targeted agents in molecularly defined subgroups before these agents can be recommended in the adjuvant setting.     

Advances in our understanding of postoperative adjuvant chemotherapy in resectable non-small-cell lung cancer

PURPOSE OF REVIEW: After publication in 1995 of a meta-analysis of adjuvant chemotherapy in the treatment of NSCLC, a number of randomized trials investigated adjuvant chemotherapy using more active chemotherapeutic regimens and larger numbers of accrued patients per trial. This review will focus on recent clinical trials for adjuvant chemotherapy, and will help to interpret the applicability of these results to daily clinical practice. RECENT FINDINGS: Four large-scale randomized trials that used platinum-based chemotherapy have reported positive results during the last 3 years. These trials included cisplatin-based chemotherapy [the International Adjuvant Lung Cancer (IALT) trial], cisplatin plus vinorelbine [the National Cancer Institute of Canada (NCIC) BR10 trial], and carboplatin plus paclitaxel [the Cancer and Leukemia Group B (CALGB) 9633 trial]. More recently, another adjuvant trial [Adjuvant Navelbine International Trialist Association (ANITA)] was reported, which has added greatly to our understanding of the potential role of adjuvant treatment. Regarding adjuvant UFT (tegafur and uracil) chemotherapy, an individual patient data-based meta-analysis demonstrated its significant effect on survival in selected patients with completely resected non-small-cell lung cancer. SUMMARY: Recent trials indicate a survival benefit of postoperative adjuvant chemotherapy. These findings are anticipated to change the clinical management of patients with completely resectable non-small-cell lung cancer.     

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.The ASCO-JSCO Joint Symposium was held in Kyoto, Japan, on October 29, 2004.     

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non–small-cell Lung Cancer

BackgroundComplete resection of non–small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection.Materials and MethodsThe LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested.ResultsThe majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and β-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches.ConclusionsImmunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.     

Adjuvant chemotherapy in early-stage non-small cell lung cancer

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.     

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.     

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.     

Adjuvant treatment of lung cancer: current status and potential applications of new regimens

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers diagnosed worldwide. Surgical resection offers the best chance for cure for those patients diagnosed with early-stage disease; however, the vast majority of patients will eventually relapse. Despite complete surgical resection, recurrences are likely due to undetectable microscopic disease at diagnosis, making these patients potential candidates for effective adjuvant therapy. Postoperative radiation therapy may actually have a detrimental effect in patients with NO-N1 disease and has been shown to possibly prevent local recurrences in patients with N2 disease. Although results from a large meta-analysis of data on adjuvant chemotherapy suggested an absolute benefit of 5% at 5 years from cisplatin-based chemotherapy, a rate similar to that seen in breast and colon cancers where adjuvant chemotherapy is a standard of care, the use of adjuvant therapy in NSCLC remained controversial. In addition, results of the International Adjuvant Lung Cancer Trial (IALT), which compared adjuvant cisplatin-based chemotherapy to observation in patients with resected stage-I-IIIA NSCLC, suggested that adjuvant therapy had the potential to prevent a substantial number of deaths each year. Two recently reported landmark studies have demonstrated the survival advantages of adjuvant therapy for patients with early-stage NSCLC. Docetaxel, one of the most active agents for advanced NSCLC, is also regularly used for locally advanced disease as part of neoadjuvant or combined-modality regimens. As recent findings have established the value of adjuvant chemotherapy for early-stage NSCLC, agents such as docetaxel warrant rigorous evaluation in this setting.     

Adjuvant treatment of stage IB NSCLC: the problem of stage subset heterogeneity

While 5-year survival rates in patients with stage IB non-small-cell lung cancer (NSCLC) are historically modest (40% to 67%), adjuvant chemotherapy trials including this subgroup have shown little evidence of chemotherapeutic benefit. This article reviews the available data regarding adjuvant chemotherapy following surgically resected stage IB NSCLC, framed within the context of present and future proposed definitions of this diagnosis. The discussion addresses limitations of the current staging system and how this contributes to the mixed results seen with adjuvant treatment. In addition, the authors consider current treatment options for stage IB NSCLC and review planned clinical trials for stage I disease designed to exploit new pharmacogenomic findings.     

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.     

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.     

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

BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.     

Treatment of patients with early epithelial ovarian cancer

PURPOSE OF REVIEW: During 2003, the first randomized trials were published comparing adjuvant platin-based chemotherapy versus no treatment in early epithelial ovarian cancer. RECENT FINDINGS: Recent findings of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm and International Collaborative Ovarian Neoplasm-1 trials showed an improvement of overall survival of 8% in patients treated with adjuvant platin-based chemotherapy compared with observation. In a subgroup analysis, in 150 optimally surgically staged patients of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm trial, there appears to be no benefit of adjuvant chemotherapy. In past years, it has been shown that degree of differentiation is a much stronger predictor of recurrence in early ovarian cancer than International Federation of Gynaecology and Obstetrics subclassification (Ia, Ib, Ic). It has also been shown that patients with bilateral tumors (Ib) have the same prognosis as International Federation of Gynaecology and Obstetrics stage Ic patients. SUMMARY: During the past year, it has been shown that platin-based adjuvant chemotherapy improves recurrence-free and overall survival in early epithelial ovarian cancer. It should be emphasized, however, that this was demonstrated in patients in whom the true nature of early stage disease was doubtful in many patients due to incomplete surgical staging. In a subgroup of patients who are optimally surgically staged, adjuvant chemotherapy may be less effective. Theoretically, only a future trial randomizing optimal surgical staging versus adjuvant chemotherapy may be able to provide definitive conclusions, but such a trial would be almost impossible to conduct. In the meantime, optimal staging is advocated in all patients who are fit enough to undergo this procedure. Degree of differentiation should be incorporated in a new International Federation of Gynaecology and Obstetrics classification for stage I disease and in clinical decision making.     

Adjuvant chemotherapy for non-small cell lung cancer

Nearly half of all patients who undergo surgical resection of localized non-small cell lung cancer (NSCLC) will develop and ultimately die of recurrent disease. The postoperative radiotherapy (PORT) meta-analysis showed adjuvant thoracic radiotherapy to have a detrimental effect on survival in this patient population. A meta-analysis of early trials of adjuvant chemotherapy by the Non-Small Cell Lung Cancer Collaborative Group showed that while chemotherapy with alkylating agents was also detrimental, chemotherapy with cisplatin-based adjuvant chemotherapy was associated with an improved hazard ratio for death (HR = 0.87), equating to a 5 percent survival benefit at 5 years. However, the result was not statistically significant (p = 0.08). Recently, results have been reported for several large Phase III trials of adjuvant chemotherapy which differed with respect to the stage of resected disease included, the type of chemotherapy used and the use of post-operative radiotherapy. Three trials (IALT, JBR 10, and ANITA) that utilized cisplatin-based doublets showed a significantly positive survival benefit of adjuvant chemotherapy in patients with Stage II-IIIA NSCLC. The magnitude of this benefit, which was suggested to be 4-5 percent at 5 years in the meta-analysis and by the IALT study, may be as large as 8-15 percent as indicated by more recent studies with modern platinum-based doublet chemotherapy. These data indicate that medically fit patients with resected Stage II-IIIA NSCLC should be offered adjuvant chemotherapy with a modern cisplatin-based doublet.     

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.