Role of multimodality treatment for lung cancer

Locally advanced non-small cell lung cancer (NSCLC) is, in fact, a systemic disease requiring a multimodality approach for optimal treatment. The role of preoperative chemotherapy has been established and is now an accepted treatment for resectable Stage IIIA NSCLC. Several studies have addressed the feasibility and efficacy of preoperative chemotherapy followed by surgery. All these induction chemotherapy trials have reported a high radiographic response rate, high respectability rate and improved survival in completely resected patients. The findings of three published randomized trials indicate that the survival rate of Stage IIIA patients is better with induction chemotherapy plus surgical resection than with resection alone. More recently, Phase II trials using concurrent chemoradiotherapy have been tested with encouraging results. Chemo-therapy combined with thoracic radiotherapy has emerged as a primary treatment option for locally advanced, unresectable NSCLC. Randomized trials and subsequent meta-analyses have shown a clear survival benefit with platinum-based combination chemotherapy administered with thoracic radiation-as compared to radiation alone-in treating inoperable Stage IIIA and IIIB lung cancer. Combined modality treatment in locally advanced NSCLC continues to evolve and is the subject of ongoing research. Despite clinical advances, many aspects of the management of these patients are yet to be fully clarified: Is surgical resection really necessary for Stage IIIA patients? What is the value of altered-fractionation radiotherapy and three-dimensional conformal radiation therapy? What is the optimal sequencing of radiotherapy and chemotherapy? In this regard, new chemotherapeutic agents may provide additional benefits in the multimodality approach, and it is for this reason that various studies are underway which have incorporated new agents in the front line setting. Finally, a better understanding of the biology of tumors could well help us to optimize treatments. In the future, molecular classification of NSCLC may provide a useful tool when making therapy-related decisions.     

Induction chemotherapy followed by radical local therapy for locally advanced non-small cell lung cancer

Many patients who receive a diagnosis of non-small cell lung cancer (NSCLC) have locally advanced disease at initial presentation. Historically, these patients were treated with primary thoracic radiation therapy and had poor long-term survival rates, secondary to both progression of local disease and development of distant metastases. With the goal of improving clinical outcomes, multiple concepts of combined-modality therapy for locally advanced NSCLC have been investigated. The rationale for using chemotherapy in the induction regimen is to eliminate subclinical metastatic disease while improving local control. The optimal treatment of locally advanced NSCLC continues to evolve, but combined-modality therapy has led to improved survival rates compared to treatment with radiation alone and has become the new standard of care. This report reviews the major trials that have investigated various combinations of surgery, radiation therapy, and chemotherapy in the treatment of locally advanced NSCLC.     

Cooperative Group Portfolio in Locally Advanced Non–Small-Cell Lung Cancer: Are We Making Progress?

Combined-modality therapy has emerged as the standard of care for fit patients with unresectable, locally advanced non-small-cell lung cancer (NSCLC). Concurrent chemotherapy/radiation has demonstrated therapeutic superiority compared with sequential or asynchronous chemotherapy and radiation in this setting. The role of consolidation or maintenance therapy with targeted agents or conventional cytotoxic agents remains unclear. We explore the portfolio of clinical trials being conducted in locally advanced NSCLC by North American cooperative oncology groups as well as ongoing trials in Europe and Japan. These efforts focus on radiation dose escalation using image-guided radiation therapy as well as newer cytotoxic agents (eg, pemetrexed) and targeted therapies (eg, cetuximab, bevacizumab, and etc) thus far unexplored in this setting.     

Concurrent docetaxel and thoracic radiation in non-small-cell lung cancer

Locally advanced (stages IIIA and IIIB) non-small-cell lung cancer (NSCLC) represents approximately 25% of new cases of NSCLC diagnosed annually. The treatment strategy for these patients involves combined-modality therapy with chemotherapy and thoracic radiation. Furthermore, a subset of patients with stage IIIA disease undergo surgical resection. Docetaxel is a chemotherapy agent with activity in both first- and second-line treatment of patients with advanced NSCLC. Several recent studies have also incorporated docetaxel in the treatment of patients with stage III NSCLC as neoadjuvant therapy, alone or in combination with cisplatin or carboplatin and thoracic radiation. Docetaxel has also been used as consolidation therapy. This review will summarize the data to date on the use of docetaxel and thoracic radiation in the treatment of patients with stage III NSCLC.     

Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: A systematic review of completed and ongoing studies

Current standard for locally advanced non-small cell lung cancer (NSCLC) is combined concurrent therapy with a platinum-based regimen. Preclinical synergistic activity of pemetrexed with radiation therapy (RT) and favorable toxicity profile has led to clinical trials evaluating pemetrexed in chemoradiation regimens. This literature search of concurrent pemetrexed and RT treatment of patients with stage III NSCLC included MEDLINE database, meeting abstracts, and the clinical trial registry database. Nineteen unique studies were represented across all databases including 11 phase I studies and eight phase II studies. Of the six phase II trials with mature data available, median overall survival ranged from 18.7 to 34 months. Esophagitis and pneumonitis occurred in 0–16% and 0–23% of patients, respectively. Of the ongoing trials, there is one phase III and four phase II trials with pemetrexed in locally advanced NSCLC. Pemetrexed can be administered safely at full systemic doses with either cisplatin or carboplatin concomitantly with radical doses of thoracic radiation therapy. While results from the ongoing phase III PROCLAIM trial are needed to address definitively the efficacy of pemetrexed–cisplatin plus RT in stage III NSCLC, available results from phase II trials suggest that this regimen has promising activity with an acceptable toxicity profile.     

Gemcitabine (Gemzar®) in non-small cell lung cancer

Of the new chemotherapeutic substances of the last decade, gemcitabine (Gemzar^®, Eli Lilly) is probably the most valuable for the treatment of early and advanced stage non-small cell lung cancer (NSCLC). When used as a single agent in both chemotherapeutically pretreated and chemotherapy-naive patients, gemcitabine shows an objective tumor regression rate of approximately 20%. Gemcitabine’s unique mechanism of action and its lack of overlapping toxicity with other cytotoxic agents also define it as an ideal candidate for combination therapy. Early clinical development has included single-agent first- and second-line treatment, doublet combination regimens and incorporation into multimodality treatment strategies for operable and inoperable locally advanced nonmetastatic NSCLC. Gemcitabine/platinum-based combination chemotherapy has become the most attractive treatment standard for NSCLC patients in good clinical condition. The role of gemcitabine in the concurrent or sequential application of chemo- and radiotherapy for inoperable locally advanced NSCLC has also been addressed in several Phase I and II studies. Based on data available, gemcitabine can be safely administered in combination with radiotherapy. This review summarizes results from representative Phase I, II and III studies in order to underline gemcitabine’s clinical importance for patients suffering from early and advanced NSCLC.     

Chimioradiothérapie concomitante pour le traitement des cancers bronchiques non à petites cellules, localisés au thorax, inopérables ou non résécables

Concomitant chemoradiation is the standard strategy for unresectable locally advanced non-small cell lung cancer (NSCLC). Its modalities used currently include three-dimensional conformal techniques, allowing dose escalation and sequential and concurrent combination with new generation cytotoxic agents. Phase III trials have not demonstrated any benefit from induction and consolidation chemotherapy in this setting. New techniques of radiation may also increase the efficacy and the feasibility of radiation. The integration of targeted therapies in the management of stage III NSCLC is also under investigation. This constant progress makes chemoradiation one of the most promising combined treatments in thoracic oncology.     

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.     

Management of patients with non-small cell lung cancer and poor performance status

Opinion statement Lung cancer is the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for approximately 86% of patients with lung cancer. The two most powerful predictors of long-term outcome in patients with NSCLC are the stage and performance status (PS) at diagnosis. Although the cure rates of patients with resected stage I and II NSCLC are 50% and 40%, respectively, only 20% of patients treated with chemotherapy and radiation for locally advanced NSCLC are cured of their illness. Patients with metastatic NSCLC do not have curative potential with available therapies. Outcome for patients with NSCLC and poor PS is dismal. Patients with localized disease and poor PS are treated with radiation therapy. Patients with locally advanced NSCLC are treated with sequential chemotherapy, followed by radiation therapy. The suggested treatment options for patients with metastatic disease and poor PS are single-agent chemotherapy or supportive care.     

Clinical issues in the management of non-small-cell lung cancer and the role of platinum-based therapy

Although the benefits of chemotherapy have been established for treating non-small-cell lung cancer (NSCLC), several clinical issues remain. Currently, doublets offer the maximum benefit in terms of balancing efficacy with tolerability to patients with advanced-stage disease. The optimal duration of therapy continues to be evaluated, and several agents have emerged for treating patients with recurrent advanced NSCLC. Chemotherapy benefits for populations underrepresented in clinical trials, such as elderly patients and patients with poor performance status, also need to be established. Although combination therapy with carboplatin/paclitaxel is one regimen of choice for treating advanced NSCLC, there may be ways to optimize its delivery schedule including use of weekly administration of paclitaxel and monthly administration of carboplatin. In addition, biologic approaches are being investigated to determine if these agents may be appropriate for treating patients with advanced NSCLC and how best to administer them. In resectable stage IIIA disease, benefits of preoperative chemotherapy and chemotherapy/radiation therapy followed by surgery continue to be evaluated. Although associated with esophageal toxicity, in non-resectable stage IIIA/IIIB disease, concurrent chemotherapy/radiation therapy has emerged as the schedule of choice. Yet, benefits of higher radiation dosage need evaluation. Based on phase II studies, preoperative chemotherapy with or without radiation may benefit patients with early-stage disease, but studies have been inconclusive, yielding mixed results. Recent trials of adjuvant chemotherapy following surgical resection in early-stage NSCLC have yielded conflicting results, with some trials showing no benefit to adjuvant therapy. Trials under way will determine the future of adjuvant or induction chemotherapy in treating this patient population.     

A Phase I Study of Temsirolimus and Thoracic Radiation in Non–Small-Cell Lung Cancer

BackgroundThe addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non–small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation.Patients and MethodsThis was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC.ResultsTen patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease.ConclusionThe combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.     

Chemotherapy in non-small cell lung cancer：opportunities for advancement

Locally advanced non-small cell lung cancer (NSCLC) continues to be a challenging disease to treat. With high rates of both local and distant failures, there is significant interest in finding more biologically active chemotherapy regimens that can contribute to reduce both failures. The phase III PROCLAIM trial, recently published in the Journal of Clinical Oncology entitled“PROCLAIM: randomized phase III trial of pemetrexed–cisplatin or etoposide–cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer”, compared two different chemotherapy regimens given concurrently with radiotherapy in patients with stage III non-squamous lung cancer: pemetrexed plus cisplatin versus cisplatin plus etoposide. Both groups received con-solidation chemotherapy. After enrolling 598 of planned 600 patients, the study was stopped early due to futility as no difference was seen in the primary end-point of overall survival. Since PROCLAIM was designed as a superiority trial, these results suggest that pemetrexed regimens do not offer a clinical advantage over standard cisplatin plus etopo-side. There are some subpopulations who might still benefit from pemetrexed, especially if clinicians are concerned about myelosuppression-related adverse events. Future trials are needed to investigate novel biologic agents and irradiation techniques that can result in more durable local and distant disease control in locally advanced NSCLC.     

Paradigms in chemoradiotherapy

The efficacy of radiation in locally advanced non- small cell lung cancer (NSCLC) is limited. In a search for improving the outcome, particular attention has focused on the possibility of combining radi- ation with chemotherapy. The two most frequently used combined modality strategies include induction chemotherapy (chemotherapy preceding radiation) and concurrent chemoradiation. The former allows for drug delivery in full doses and in principle aims at a reduction of micrometastatic disease, whereas the latter is believed to improve locoregional control by making tumour cells more vulnerable to radiotherapy. The results of phase III trials of induction chemo- therapy were equivocal; nevertheless, three large trials using platinum-based regimens demonstrated significant survival benefit. The role of single agent platinum compounds (believed to be radiosensitising agents) applied concurrently with radiotherapy is controversial. Improved survival with this strategy was demonstrated in two studies, but several other studies were negative. Concurrent application of multidrug platinum-based chemotherapy in conventional sched- ules has been found relatively toxic yet feasible in selected patients. The direct comparison of sequential versus concurrent use of chemotherapy and radiation demonstrated the superiority of the latter, but at the expense of higher acute in-field toxicity. More recently, several new agents, including taxanes, vinorelbine and gemcitabine, have appeared promising in NSCLC. Their role in combined modality regimens warrants further clinical research. Chemotherapy as an adjunct to radiation has become a standard in fit patients with locally advanced NSCLC. The gain from the combined modality approach, however, is modest on average and should be weighted against increased early and late toxicity. Further studies built upon recent positive results should focus on identifying the means of optimal interactions between the two modalities. This research should define the most effective types and doses of anti-cancer agents as well as the optimal features of radiotherapy. Additionally, the knowledge of the biological characteristics of individual tumours, in particular their expected response to therapy, may contribute to further progress.     

A case of locally advanced non-small-cell lung cancer complicated with chronic renal failure and gastric cancer, successfully treated with weekly docetaxel and concurrent thoracic radiotherapy

A standard therapy is not established for locally advanced non-small-cell lung cancer(NSCLC)complicated with chronic renal failure, although some cases of the disease have been reported. We report a case of a locally advanced squamous cell carcinoma of the lung, complicated with chronic renal failure. He was successfully treated with weekly docetaxel(DOC)and concurrent thoracic radiotherapy, and no deterioration of renal function was observed. In locally advanced NSCLC complicated with renal dysfunction, treatment with weekly DOC and concurrent thoracic radiotherapy is considered to be a therapeutic option. Since radiation pneumonitis occurred in the present case, the accumulation and precise analysis of applicable cases is an important subject for future consideration.     

Treatment of locally advanced non-small cell lung cancer in the elderly

PURPOSE OF REVIEW: Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. Most cases of NSCLC are diagnosed in the advanced or locally advanced stage. It has been shown that combined chemo-radiotherapy is more efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC. However, chemo-radiotherapy, even if given with sequential approach, in clinical practice can be contraindicated in elderly patients. In fact, this patient population often present at diagnosis with cardiovascular and/or pulmonary comorbidities that increase the risk of severe side effects from chemo-radiotherapy. The present review aims at focusing the currently available evidences on the treatment of elderly patients affected by locally advanced NSCLC and at giving future perspectives on this topic. RECENT FINDINGS: Very few specific prospective data are available on the treatment of locally advanced NSCLC in the elderly. Some phase II studies suggest that low-dose chemotherapy given concurrently with radiotherapy could be safely administered to this patient population. Retrospective analyses on full-dose sequential and concurrent chemo-radiation are to be considered globally ambiguous and at risk of selection bias. SUMMARY: Only specifically designed prospective studies will elucidate the real role and feasibility of combined chemo-radiotherapy in the treatment of locally advanced NSCLC in the elderly. Future perspectives on this topic include the evaluation of alternative schedules of chemo-radiotherapy, innovative radiation techniques more suitable to elderly patients, and the introduction of new, well-tolerated, molecularly targeted agents combined with standard treatments.     

晚期非小细胞肺癌的中医维持治疗

晚期非小细胞肺癌（ＮＳＣＬＣ）维持治疗是肿瘤学专家在化疗疗效达到“瓶颈”后为延长患者生存时间所提出的一种新型治疗模式,主要包括化疗维持和靶向维持,目前维持治疗尚存在较多的争议,临床上尚未完全推行。本文通过论述中医药治疗晚期ＮＳＣＬＣ的现状及优势,分析中医药进行维持治疗的优势及可行性,并对维持治疗的发展进行探索,希望中医药在晚期ＮＳＣＬＣ维持治疗中能有新的突破和进展。     

Basic treatment considerations: chemotherapy

Lung cancer represents a major global health problem, with more than a million deaths reported each year. Because there are no effective screening tools to date, diagnosis of the disease at an advanced stage is a common feature. Over the past 20 years, elegant strides have been made in the treatment of patients with advanced NSCLC. Several novel chemotherapy agents that are efficacious and possess favorable toxicity profiles have been developed recently. In addition to evaluating novel combinations, alternative schedules to improve toxicity profiles are subjects of clinical trials. Much work needs to be done, however, to improve the outcome for patients with lung cancer. Chemotherapy extends life and improves quality of life for patients with stage IIIB/IV NSCLC. Combined modality therapy with radiation and chemotherapy improves the outcome for patients with locally advanced NSCLC and is associated with a curative potential. Molecularly targeted therapies are under rigorous evaluation, although the initial results have been disappointing. In the upcoming years, we will learn effective means to incorporate molecularly targeted therapies to existing treatment paradigms in lung cancer.     

The impact of three-dimensional radiation on the treatment of non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) patients with locally advanced unresectable disease have a grim prognosis. Radiotherapeutic strategies are necessary to improve the permanent eradication of thoracic disease. The poor results achieved with conventional external beam radiation therapy reflect in part, the inadequacy of such therapy in achieving its primary objective of achieving local control. The impact of three-dimensional conformal radiation therapy (3-DCRT) on local disease eradication and its potential role in improving survival is assessed. DESIGN: This review addresses aspects of the software and hardware technology of 3-DCRT, the clinical and technical aspects of target volume definition, the use of 3-DCRT to predict radiation pneumonitis, strategies for dose escalation in NSCLC, and analyses the clinical results to date. RESULTS: Initially investigators compared the best treatment techniques devised with conventional planning techniques to those devised with 3-DCRT. These analyses showed that 3-DCRT had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Software and hardware developments continue to develop and have the potential to solve evolving clinical issues. Dose-volume-histograms have been used to accurately quantify lung dose and derived parameters have the potential to predict the risk of pneumonitis for individual patients before treatment. Initial clinical results have been promising and strategies for further dose escalation are emerging. CONCLUSION: Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced non-small cell lung cancer.     

The role of radiation therapy in thoracic tumors

Radiation plays an important role in the treatment of thoracic tumors. During the last 10 years there have been several major advances in thoracic RT including the incorporation of concurrent chemotherapy and the application of con-formal radiation-delivery techniques (eg, stereotactic RT, three-dimensional conformal RT, and intensity-modulated RT) that allow radiation dose escalation. Radiation as a local measure remains the definitive treatment of medically inoperable or surgically unresectable disease in NSCLC and part of a multimodality regimen for locally advanced NSCLC, limited stage SCLC, esophageal cancer, thymoma, and mesothelioma.     

Management of unresectable stage III non-small cell lung cancer: the role of combined chemoradiation

Until the late 1980s, thoracic radiation therapy (TRT) was considered the standard of care for patients with stage III disease despite extremely poor 5-year survival rates. Several studies evaluating TRT combined with chemotherapy showed a survival advantage. Based on these data, combined modality therapy became accepted as the standard of care in this group of patients with good performance status and made the treatment of locally advanced non-small cell lung cancer (NSCLC) a multidisciplinary endeavor. Recent studies have shown that concurrent chemoradiotherapy offers a significantly greater survival advantage than sequential chemoradiotherapy and should be considered standard of care in stage III inoperable NSCLC. Although numerous Phase III trials have clearly demonstrated a survival benefit in those patients who receive combined modality therapy, many questions remain. The most effective combination of drugs, their optimal mode of administration, the use of either induction or consolidation therapy in addition to a backbone of concurrent therapy, and the details of TRT, including total dose, fractionation, acceleration, treatment volumes, and tumor targeting remain important issues to define. Although progress has been made in treatment for locally advanced NSCLC, the majority of patients still die within 5 years either from locoregional or distant progression of disease. This article will review the current data regarding treatment of this heterogeneous group of patients. In addition, a brief summary of new molecular therapies and chemotherapeutics will be presented.