help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 Click here to read this article as a CME course

The Oncologist, Vol. 13, No. 3, 309-319, March 2008; doi:10.1634/theoncologist.2007-0195
© 2008 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haasbeek, C. J.A.
Right arrow Articles by Lagerwaard, F. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Haasbeek, C. J.A.
Right arrow Articles by Lagerwaard, F. J.

Radiation Oncology

Critical Review of Nonsurgical Treatment Options for Stage I Non-Small Cell Lung Cancer

Cornelis J.A. Haasbeeka, Suresh Senana, Egbert F. Smitb, Marinus A. Paulc, Ben J. Slotmana, Frank J. Lagerwaarda

Departments of aRadiation Oncology, bPulmonology, and cSurgery, VU University Medical Center, Amsterdam, The Netherlands

Key Words. Lung cancer • Stage I • Surgery • Radiotherapy • Radiofrequency ablation

Correspondence: Cornelis J.A. Haasbeek, M.D., Department of Radiation Oncology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. Telephone: 31-20-4440414; Fax: 31-20-4440410; e-mail: cja.haasbeek{at}vumc.nl

Received October 15, 2007; accepted for publication January 18, 2008.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the current results obtained with primary resection in stage I NSCLC.
  2. Describe clinical outcomes with nonsurgical techniques such as stereotactic radiation therapy and radiofrequency ablation.
  3. Identify potential advantages and drawbacks of these nonsurgical techniques.
  4. Assess which patients would benefit most from these techniques.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 
Surgery has traditionally been regarded as the treatment of choice for patients with stage I non-small cell lung cancer. However, the morbidity and mortality associated with surgery in elderly patients with considerable comorbidity remains of concern, as are the poor 5-year survival rates. Until recently, conventional radiation therapy was the only alternative curative treatment option for patients who were unfit for surgery, but with lower local control rates that were inferior to those with surgery. However, a growing body of clinical data on outcomes with newer nonsurgical treatment options such as stereotactic radiation therapy (SRT) and radiofrequency ablation (RFA) is now available.

SRT is a noninvasive method showing a 2-year local control rate in excess of 85% in both T1 and T2 tumors after three to eight fractions of high-precision radiotherapy. Despite the use of very high radiation doses, high-grade toxicity is limited to approximately 5% of patients. Percutaneous RFA is an invasive method showing 2-year local control rates of approximately 64% in smaller tumors, but results are poorer in lesions ≥3 cm. Compared with SRT, a higher procedure-related morbidity and mortality rate has been reported, mainly caused by pneumothorax and hemorrhage. Although data from randomized trials of conventional radiotherapy versus SRT or RFA are not available, the use of SRT is becoming widespread for patients who are unfit for surgery. Reported 2-year local control rates after SRT are comparable with those achieved with surgery, and prospective randomized trials comparing surgery with SRT in patients who are fit to undergo surgery are now being planned.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, with over 1 million deaths every year [1]. Only about 20% of patients present with stage I disease (tumor–node–metastasis [TNM] stage T1–2N0M0) [2], but even after complete surgical excision, the 5-year survival rate is <70% as a result of tumor recurrence, noncancer-related mortality, and second malignancies [3–5]. Large differences in outcome are observed within stage I after surgery, with 5-year overall survival rates ranging from 77% for small T1 tumors to 35% for large T2 tumors [6].

Surgery is the current standard of care for patients with stage I NSCLC [7], but can be associated with significant morbidity and even mortality, particularly because patients suffering from lung cancer are often elderly with high comorbidity rates [8]. Age itself is an independent predictor of postsurgical survival in NSCLC patients, even after adjustment for significant covariates [9]. A wait-and-see policy is inappropriate in patients who are unfit for surgery because the 5-year overall survival rate in untreated stage I NSCLC patients is in the range of 6%–14% [10, 11], with a 5-year disease specific survival rate of only 23% for T1 tumors [11]. Given a median survival duration of 9–14 months, it is recommended that surgical resection or other ablative therapies not be delayed for even small lung tumors. Newer nonsurgical treatments with high cure rates will clearly have a major impact on outcomes in patients at high risk for surgical morbidity. This review highlights the drawbacks of surgery as a treatment option (Table 1) and critically reviews new developments in nonsurgical treatments for stage I NSCLC.


View this table:
[in this window]
[in a new window]

  		Table 1. Why are alternatives to surgery needed in stage I non-small cell lung cancer?

 

   SURGERY
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 
Mortality
Surgery is associated with a 30-day postoperative mortality rate in the range of 1%–5% for lobectomy and up to 10% after right-sided pneumonectomy (Table 2). A study in the U.S. revealed that survival was superior for patients undergoing resection at hospitals where many procedures were performed, compared with survival in centers performing a smaller number of lung-resection procedures [12]. Recent studies reported lower mortality rates after surgery for lung cancer, a finding that may reflect improved perioperative patient care. For example, the American College of Surgeons Oncology Group Z0030 trial reported an overall operative mortality rate of only 1.4% for lobectomy and 4% for pneumonectomy. Nevertheless, 38% of patients developed major complications, with the most common being atrial arrhythmias, prolonged air leaks, and prolonged chest tube drainage. Such complications are significant as they prolong hospitalization and have a major adverse impact on patients [13]. Similarly, a retrospective multicenter series from Japan by Wada et al. [14] on 7,000 resections showed a 1.3% mortality rate overall and a 3.2% mortality rate after pneumonectomy.


View this table:
[in this window]
[in a new window]

  		Table 2. Thirty-day postsurgical mortality for early-stage lung cancer

 
Postsurgical Recurrences
The International Association for the Study of Lung Cancer Lung Cancer Staging Project analyzed a large international database and reported 5-year survival rates of 77% and 71% after radical excision of pT1N0 tumors ≤2 cm (pT1a; n = 1,816 patients) and tumors 2–3 cm, respectively (pT1b; n = 1,653 patients) [6]. The corresponding 5-year survival rates for pathologically staged T2N0 tumors measuring 3–5 cm (pT2a; n = 2,822), 5–7 cm (pT2b; n = 825), and >7 cm (pT2c; n = 364) were 58%, 49%, and 35% (p < .0001), respectively. When examining survival rates according to clinical stage instead of pathological stage, the 5-year survival rates were as low as 53% for T1a and 26% for T2c tumors.

Between 20% and 30% of patients develop recurrence after surgery for stage I NSCLC, despite preoperative staging using fluorodeoxyglucose positron emission tomography (FDG-PET) scans [15]. Most recurrences develop at distant sites, including pulmonary, brain, bone, and adrenal gland metastasis. Locoregional recurrences occurred in 12% of patients in the series of Martin-Ucar et al. [16] after a median follow-up of 4 years following lobectomy. Comparable results were reported by Martini et al. [3] in 598 patients who were followed up for a median of 7.6 years. The majority (20%) developed systemic recurrences; locoregional disease manifested in 7% [3]. Sixty percent of all recurrences developed within 2 years, and only 9% developed after ≥5 years.

After surgical resection, second primary lung tumors are reported to occur at a rate of 1%–2% per patient-year [3]. The cumulative risk for second lung tumors and other smoking-related cancer increases and reaches 15%–20% at 8 years after resection [3, 17]. In cases where initial surgical treatment has led to a reduction in quality of life (QoL) or pulmonary reserve, a patient's ability to undergo curative treatment for a second tumor may be restricted. A previous tumor at any site is an independent prognostic factor that increases the probability of death by 1.5 times at 5 years, independent of other comorbidities, TNM classification, and age [18].

Extent of Resection
Although lobectomy is considered the standard surgical procedure in stage I lung cancer, 5%–15% of patients require a bilobectomy and 5%–15% require a pneumonectomy [13, 19, 20]. If extensive surgery is required for a central tumor, a sleeve resection is preferred over a pneumonectomy because of better postoperative pulmonary function [21]. In frail patients who may not be able to tolerate lobectomy, a more limited procedure, that is, a segmentectomy or wedge resection, is used, although data regarding local control are inconsistent [3, 22–24]. One report suggested that local recurrences may be more frequent after limited resection in tumors >3 cm [25]. A randomized trial by the Lung Cancer Study Group suggested that a threefold higher local failure rate occurred in patients who underwent limited resection versus lobectomy, but reanalysis of the data revealed no significant differences in overall survival [22, 26]. Similarly, a recent meta-analysis on the published literature reported comparable survival rates with both limited resection and lobectomy for stage I lung cancer, but advised caution in interpretation of the results because interstudy heterogeneity was detected [27].

A procedure that may reduce the morbidity associated with open thoracotomy, especially postoperative pain, is the use of video-assisted thoracoscopic surgery (VATS) [28]. VATS and open thoracotomy have been compared in small studies, where the procedure was reported not to have detrimental effects on local control or overall survival [29–31]. Although VATS has been in use since the 1990s, this procedure was only performed in 10% of patients included in a recent large multi-institutional study [13]. The safety and efficacy of VATS remain to be confirmed in larger randomized trials [32].

QoL After Surgery
Surgery is associated with loss of pulmonary function and exercise capacity in the range of 10%–40%, depending on the extent of the resection and time elapsed since surgery [33–35]. Respiratory symptoms and pain are important factors resulting in the frequent deterioration in QoL after surgery [36, 37]. Post-thoracotomy pain is a frequent symptom, persisting for >4 years in approximately 30% of patients [38], and 5% of patients experience severe and disabling post-thoracotomy pain syndromes [39]. In the planned randomized trials of surgery versus noninvasive techniques, QoL will have to be one of the major study endpoints, because the morbidity and mortality associated with surgery, and subsequent deterioration in QoL, are the most important reasons to search for less invasive treatment alternatives.

Greater Toxicity in Elderly Patients
Approximately 45% of the patients presenting with lung cancer are aged ≥70 years at the time of diagnosis [40]. Although advanced age is not an absolute contraindication for surgery, significant comorbidity is observed in approximately 70% of lung cancer patients in the age group ≥70 years [8]. Frequent comorbidities, such as cardiovascular disease and severe chronic obstructive pulmonary disease, result in higher perioperative morbidity and mortality rates after open thoracotomy in older patients [41]. The postoperative mortality rate is only 1.7% in patients <60 years of age and 9.4% in octogenarians [42]. More limited resections have been recommended in frail elderly patients, because any increase in local recurrences in elderly patients may be balanced by less surgical morbidity and mortality [41]. Analysis of the Surveillance, Epidemiology, and End Results database revealed no differences in long-term survival between lobectomies and limited resections in patients >70 years old [9].

Even with the problems stated above and the absence of randomized clinical trials to support its use, the role of surgery as a standard treatment is supported by observational data showing higher local control and survival rates than with conventionally fractionated radiation therapy [7, 43]. However, the benefits and especially the toxicity of surgery need to be weighed constantly against those of new, less invasive treatment approaches, especially in elderly patients at high risk for surgical morbidity (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 3. Which patients are at high risk for surgical morbidity?

 

   CONVENTIONAL RADIATION THERAPY
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 
Until recently, conventional radiation therapy was the preferred treatment in patients with stage I NSCLC who were unfit to undergo surgery or who declined surgery. This is, however, a poor alternative to surgery in operable patients because the mean reported crude local recurrence rates are as high as 40% (range, 6%–70%), resulting in 3-year overall and cause-specific survival rates of 34% and 39%, respectively [43]. Conventional radiotherapy involves daily treatment sessions over a 5- to 7-week period, and inadequate local tumor control is mainly the result of insufficiently high doses and target miss caused by tumor mobility [44].


   NEW NONINVASIVE OR MINIMALLY INVASIVE TECHNIQUES
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
Future Developments
 Conclusions
 References
 
Stereotactic Radiation Therapy
Stereotactic radiation therapy (SRT) was first developed in the 1950s for the treatment of intracranial lesions. Technological developments in planning and treatment delivery of radiation therapy in the last decade have led to the application of this technique to extracranial sites including the thorax and abdomen. SRT is a form of high-precision radiotherapy delivery characterized by (a) reproducible immobilization to avoid patient movement during treatment sessions; (b) measures to account for tumor motion during imaging, treatment planning, and radiation delivery; (c) use of dose distributions tightly covering the tumor, with rapid dose falloff in surrounding normal tissues in order to reduce toxicity; and (d) most importantly, the use of extremely high doses of radiation usually delivered in three to eight treatment fractions within a 2-week period [45].

The radiation schedules used in SRT cannot be simply compared with those used in conventional schemes by comparing total dose, because the dose per fraction is not identical. However, the relative efficacy of radiotherapy fractionation schemes can be predicted and compared by calculating the biologically effective dose (BED) [46]. Conventionally fractionated schedules typically use doses with a BED of 70–80 Gy. Modern SRT schedules use dose schedules equivalent to a BED ≥100 Gy, resulting in superior tumor kill. Several fractionation schedules are undergoing evaluation, and a frequently used schedule for peripheral lung tumors is three fractions of 20 Gy, equivalent to a BED as high as 180 Gy [47].

The results and toxicity of SRT reported by studies in which at least 40 patients with stage I NSCLC were included are summarized in Table 4. Typical local control rates with schedules using a BED >100 Gy are approximately 90%. The largest series were reported from Japan [48, 49], Scandinavia [50], the U.S. [47], and the Netherlands [51], comprising experience in over 750 patients. The largest series was published by Onishi et al. [49] and retrospectively described the results of 257 patients treated in 14 institutions in Japan [52], using a number of different treatment doses and delivery approaches. At a median follow-up of 38 months (range, 2–128 months), the local recurrence rate was 8.4% in patients who were treated to a BED of ≥100 Gy. As with radiofrequency ablation (RFA), most reports on outcomes with SRT have been in patients who are unfit to undergo surgery, and include only a minority of patients who refused surgery. This introduces a large selection bias compared with surgery, rendering overall survival less suitable for comparison. This Japanese study, however, also included nearly 100 patients who refused surgery, and the 5-year overall survival rate of 70.8% observed after a BED of 100 Gy among those patients is at least equivalent to the outcome after surgery [6, 24, 53]. More than 350 patients have undergone SRT at the VUmc University Medical Center since 2003. The results of the first 197 patients with a total of 210 primary lung tumors for local control and toxicity were recently reported by Lagerwaard et al. [51]. All patients were treated to a BED >100 Gy in three to eight fractions. The median follow-up time was 12 months (range, 3–44 months). Local relapse was observed in six patients, resulting in an actuarial 2-year local control rate of 94%, with no significant difference in local control between T1 and T2 tumors.


View this table:
[in this window]
[in a new window]

  		Table 4. Results of SRT in the treatment of stage I NSCLC

 
Response evaluation after SRT can be difficult because fibrosis and subclinical radiation pneumonitis are frequently observed, and establishing local control requires careful radiological follow-up. FDG-PET is of limited value in distinguishing fibrosis from tumor recurrence because treated volumes can show 18F-FDG uptake for at least 12 months after treatment [54]. Careful radiological follow-up of patients is paramount in patients who are treated using SRT, because salvage surgery or mediastinal radiation therapy might still be possible in cases of local or regional recurrence.

Toxicity of SRT
Reported long-term toxicities exceeding grade II (National Cancer Institute – Common Toxicity Criteria version 3) are limited to <10% of patients, and were mainly observed with large or centrally located tumors [47, 55]. In the series by Onishi et al. [49], pulmonary complications exceeding grade 2 were observed in 14 patients only (5.4%). Timmerman et al. [55] reported the need for caution when a BED of 180–210 Gy was administered for centrally located tumors adjacent to the mediastinum. In the patients treated by Lagerwaard et al. [51], using a "risk-adapted" approach with the BED limited to 105 Gy for central tumors, early toxicity was mild, with fatigue (32%), nausea (10%), and chest pain (8%) as the most frequently encountered acute side effects. Late toxicity was uncommon, with radiation pneumonitis exceeding grade 2 in six patients only (3%). Rib fractures and chronic pain syndromes located at the chest wall were observed in three patients each. Other authors have shown that a BED >100 Gy is sufficient to achieve local control [56], thereby justifying the continued treatment of central tumors at lower SRT doses.

As postsurgical deterioration in QoL is of concern, special attention has been paid to post-SRT changes in QoL measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13 Lung Cancer Modules [57]. Early analysis of these data indicates that the high local control rates achieved by the high radiation doses in SRT are not accompanied by changes in QoL. Serial measurements of pulmonary function after SRT show no significant decreases in total lung capacity, vital capacity, or forced expiratory volume in 1 second [58, 59]. These findings are also relevant with regard to the treatment of second primary lung tumors or late recurrences.

RFA
RFA is a well-established modality in the treatment of unresectable liver tumors, in both primary malignancies and metastases [60]. Recently, several authors have evaluated RFA for the treatment of small primary lung tumors and lung metastases in patients who are medically inoperable [61]. During RFA, a radiowave-emitting probe is inserted into the tumor under computed tomography (CT) guidance and is used to heat the tumor to 90–100°C, resulting in focal coagulation necrosis. Most published reports on RFA for lung lesions have described the techniques used and short-term complications, but data on long-term local control are mainly limited to patients with metastatic lesions, and are not widely available for patients with stage I NSCLC. RFA is generally not recommended for centrally located tumors, although experience is increasing [62]. Positioning the RFA electrode in small apical lung tumors, in posteriorly located tumors close to the diaphragm, and in tumors in the proximity of the scapula is technically difficult [63]. The local control rate using RFA appears comparable with that using conventionally fractionated radiation therapy, but varies widely depending on the tumor size (Table 5). In the largest reported series, which evaluated 153 patients, local control at 2 years ranged from 25% for T2 tumors to 64% for T1 tumors [64]. In one series of selected patients with small tumors, local control up to 93% at 18 months was reported, but this series included mostly patients with pulmonary metastasis and only nine patients with a primary stage I lung tumor [65].


View this table:
[in this window]
[in a new window]

  		Table 5. Results of RFA in the treatment of stage I NSCLC or metastasis

 

Toxicity of RFA
The most frequent complication of RFA is pneumothorax, which requires chest tube insertion in 10%–20% of patients. The largest reported series, by Simon et al. [64], observed an overall 30-day mortality rate of 3.9%, with a procedure-specific mortality rate of 2.6%. Similar morbidity rates were reported by other authors [65–67], and a short period of hospitalization is required in approximately 10% of patients because of pneumo- or hematothorax, hemoptysis, bronchopleural fistulas, or abscess formation. The data currently available suggest that the toxicity profile of RFA is not unfavorable in comparison with the complications of limited surgery in high-risk patients. A significant new development is an alert issued by the U.S. Food and Drug Administration (FDA) on mortality observed with the use of RFA for lung lesions [68]. It was pointed out that RFA equipment has not been cleared by the FDA for this indication, and the FDA recommended that this treatment not be used outside clinical trials until more clinical safety data are available.


   FUTURE DEVELOPMENTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
Conclusions
 References
 
Staging and Screening in Early-Stage NSCLC
The number of patients with early-stage NSCLC is expected to increase as a result of screening programs, technological advances in imaging including FDG-PET/CT, and the more widespread use of CT scans for various other indications. No survival benefit has yet been proven for the use of screening CT scans in populations at high risk for lung cancer, but randomized trials, like the National Lung Screening Trial and the NELSON Trial, are still ongoing [69]. Superior staging techniques like FDG-PET can improve identification of true early-stage disease by excluding patients with otherwise occult metastatic disease [70].

A diagnosis of lung cancer is not always histologically established before surgery, even when using a full clinical workup including bronchoscopic and CT-guided biopsy. Use of CT screening in Japan has led to an increase in the number of patients in whom no histopathological confirmation was obtained before surgery, from 30% to 50% [71]. The authors attributed this finding to the increased prevalence of smaller CT-detected tumors, which are less accessible by needle biopsy. Consequently, pathology in excised lesions revealed the presence of benign disease in 13% of cases. The likelihood of inadvertently treating benign disease can be reduced by applying the Swenson criteria (age, smoking history, previous cancer, tumor diameter, spiculation, and tumor location [72]), combined with the results of FDG-PET [73], in order to estimate the probability of malignancy. Although the chance of treating benign disease is likely to be <5% when including FDG-PET in the pretreatment workup [74], a cytological or histological diagnosis is still recommended, where possible, for both surgical and nonsurgical treatment.

The ability to predict the likelihood of malignancy may be further increased in the future by using cytopathology combined with gene-expression profiling in normal lower airway cells obtained at bronchoscopy, with a reported 95% sensitivity and a 95% negative predictive value for lung cancer [75]. Advances in proteomics might also bring a clinically usable diagnostic tool, analyzing protein expression levels in blood or other tissue samples [76]. The use of bronchoscopy in screening, especially in combination with endobronchial optical spectroscopy or autofluorescence, will increase the incidence of early-stage endobronchial disease [77, 78]. This could be a valuable development, because extensive surgical resection can often be prevented in these patients by the use of local endobronchial treatment modalities, including photodynamic therapy, brachytherapy, electrocautery, cryotherapy, and neodymium-doped yttrium aluminum garnet laser, which are increasingly used not only for palliation of late obstructing cancers but also for primary treatment of early-stage endobronchial disease [79–81].

Adjuvant Chemotherapy
Up to 50% of patients with stage IB NSCLC eventually develop disease recurrence despite initial local treatment with curative intent. Cisplatin-based chemotherapy was shown in a meta-analysis to produce a survival benefit in patients with stage II and higher disease [82]. However, no significant survival advantage was seen in stage IB disease, and a disadvantage for chemotherapy was observed in patients with stage IA disease. A method for the selection of patients with stage IB or even stage IA disease who could potentially benefit from adjuvant treatment could be a valuable development. Efforts are being made to estimate the likelihood of relapse based on genetic profiling, and initial findings show that genetic profiling might be a better predictor of disease recurrence and survival than classic clinical staging [83, 84]. An additional method to estimate the probability of disease recurrence might be the use of FDG-PET, because the level of FDG uptake in the primary lung tumor appears to be predictive of disease-free survival [85]. An alternative way to increase the therapeutic gain of adjuvant therapy is not to predict the likelihood of disease relapse, but to predict the likelihood of drug resistance, for example, by the measurement of excision repair cross-complementation group 1 (ERCC1) gene expression. ERCC1 encodes for a protein needed in the repair of DNA damage caused by platinum-based chemotherapy such a cisplatin, carboplatin, and oxaliplatin. Only ERCC1-negative patients might benefit from platinum-based chemotherapy [86].

Selecting patients with a combination of a high probability of disease recurrence and a high probability of drug sensitivity might show a benefit of adjuvant chemotherapy even in early-stage disease.

Planning Clinical Trials of New Techniques Versus Surgery
Although the median follow-up duration is relatively short, the available data on SRT suggest that local control using SRT might be equivalent to that with surgery, with a superior toxicity profile. Phase II and III trials are in preparation in the U.S., The Netherlands, and Japan. The formal staging of NSCLC in the upcoming TNM update will remain unchanged for early-stage disease [6, 87, 88], but treatment strategies may evolve to take into account the different prognostic subgroups of stage I disease.

Some issues that need to be accounted for in the design of these studies are (a) sufficiently long follow-up in order to establish locoregional control and survival as well as late treatment toxicity, including QoL measurements and lung function testing, because less treatment toxicity is the main reason to test alternatives to surgery; (b) differences in the approach to mediastinal lymph nodes (no treatment during SRT compared with mediastinal lymph node dissection in the surgery arm), thus introducing differences in regional failure as a possible study endpoint; (c) long-term frequent radiological follow-up for patients treated using SRT in order to distinguish radiation-induced fibrosis from local recurrences, and for the evaluation of regional control, especially as patients might be eligible for salvage treatment; and (d) the inclusion of patients without histopathological proof of malignancy.

As about half of patients are operated upon without histological proof [71], many patients with smaller tumors may be excluded from these trials if histological proof was mandatory. In selected populations where the incidence of atypical infections is unlikely, a combination of clinical and radiological tumor characteristics, combined with the use of FDG-PET, can reduce the likelihood of treating benign disease to <5% [73, 74]. In such cases, an option would be to include patients without a cyto- or histopathological diagnosis in randomized studies as long as careful monitoring of the surgical patients does not show an unacceptable percentage of benign disease.


   CONCLUSIONS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
References
 
The current standard of care for patients with stage I NSCLC is an anatomical surgical resection that achieves local control in most patients, but which is associated with a risk for significant morbidity. New minimally invasive or noninvasive treatment options, including SRT and RFA, have been explored as alternatives in patients who are unfit for surgery. Local control with SRT even appears to be comparable with that achieved with surgery, but with far lower complication rates. In view of the toxicity and mortality observed after RFA, the safety of this treatment for lung tumors requires further evaluation before use outside clinical trials. A potential drawback of SRT is that it is not yet widely available, as well-trained staff and modern image-guided linear accelerators are required to deliver this treatment.

Randomized trials comparing surgery with SRT in the operable patient group are eagerly awaited. Until such time that these data become available, SRT should be strongly considered as a treatment option in all patients who are at high risk for surgical morbidity.


   FOOTNOTES
 
Conception/design: Cornelis J.A. Haasbeek, Suresh Senan, Frank J. Lagerwaard

Collection/assembly of data: Cornelis J.A. Haasbeek, Suresh Senan, Frank J. Lagerwaard

Data analysis and interpretation: Cornelis J.A. Haasbeek, Suresh Senan, Egbert F. Smit, Marinus A. Paul, Ben J. Slotman, Frank J. Lagerwaard

Manuscript writing: Cornelis J.A. Haasbeek, Suresh Senan, Egbert F. Smit, Marinus A. Paul, Ben J. Slotman, Frank J. Lagerwaard

Final approval of manuscript: Cornelis J.A. Haasbeek, Suresh Senan, Egbert F. Smit, Marinus A. Paul, Ben J. Slotman, Frank J. Lagerwaard


   REFERENCES
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Conventional Radiation Therapy
 New Noninvasive or Minimally...
 Future Developments
 Conclusions
 References
 

  1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–543.[CrossRef][Medline]
  2. Little AG, Gay EG, Gaspar LE et al. National survey of non-small cell lung cancer in the United States: Epidemiology, pathology and patterns of care. Lung Cancer 2007;57:253–260.[CrossRef][Medline]
  3. Martini N, Bains MS, Burt ME et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120–129.[Abstract/Free Full Text]
  4. Goya T, Asamura H, Yoshimura H et al. Prognosis of 6644 resected non-small cell lung cancers in Japan: A Japanese lung cancer registry study. Lung Cancer 2005;50:227–234.[CrossRef][Medline]
  5. Duque JK, Lopez-Encuentra A, Rami-Porta R. Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery. Survival of 2,991 patients with surgical lung cancer: The denominator effect in survival. Chest 2005;128:2274–2281.[CrossRef][Medline]
  6. Rami-Porta R, Ball D, Crowley J et al. International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: Proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:593–602.[CrossRef][Medline]
  7. Manser R, Wright G, Hart D et al. Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev 2005;(1):CD004699.
  8. Janssen-Heijnen ML, Schipper RM, Razenberg PP et al. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: A population-based study. Lung Cancer 1998;21:105–113.[CrossRef][Medline]
  9. Mery CM, Pappas AN, Bueno R et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the Surveillance, Epidemiology, and End Results database. Chest 2005;128:237–245.[CrossRef][Medline]
  10. Wisnivesky JP, Bonomi M, Henschke C et al. Radiation therapy for the treatment of unresected stage I-II non-small cell lung cancer. Chest 2005;128:1461–1467.[CrossRef][Medline]
  11. Raz DJ, Zell JA, Ou SH et al. Natural history of stage I non-small cell lung cancer: Implications for early detection. Chest 2007;132:193–199.[CrossRef][Medline]
  12. Bach PB, Cramer LD, Schrag D et al. The influence of hospital volume on survival after resection for lung cancer. N Engl J Med 2001;345:181–188.[Abstract/Free Full Text]
  13. Allen MS, Darling GE, Pechet TT et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: Initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 2006;81:1013–1019; discussion 1019–1020.[Abstract/Free Full Text]
  14. Wada H, Nakamura T, Nakamoto K et al. Thirty-day operative mortality for thoracotomy in lung cancer. J Thorac Cardiovasc Surg 1998;115:70–73.[Abstract/Free Full Text]
  15. Gauger J, Patz EF Jr, Coleman RE et al. Clinical stage I non-small cell lung cancer including FDG-PET imaging: Sites and time to recurrence. J Thorac Oncol 2007;2:499–505.[Medline]
  16. Martin-Ucar AE, Nakas A, Pilling JE et al. A case-matched study of anatomical segmentectomy versus lobectomy for stage I lung cancer in high-risk patients. Eur J Cardiothorac Surg 2005;27:675–679.[Abstract/Free Full Text]
  17. Pasini F, Verlato G, Durante E et al. Persistent excess mortality from lung cancer in patients with stage I non-small-cell lung cancer, disease-free after 5 years. Br J Cancer 2003;88:1666–1668.[CrossRef][Medline]
  18. Lopez-Encuentra A, Gomez de la Camara A, Rami-Porta R et al. Previous tumour as a prognostic factor in stage I non-small cell lung cancer. Thorax 2007;62:386–390.[Abstract/Free Full Text]
  19. Birim O, Kappetein AP, Goorden T et al. Proper treatment selection may improve survival in patients with clinical early-stage nonsmall cell lung cancer. Ann Thorac Surg 2005;80:1021–1026.[Abstract/Free Full Text]
  20. Daniels JM, Eerenberg JP, Rijna H et al. Mitotic index does not predict prognosis in stage IA non-small cell lung cancer. Lung Cancer 2002;38:163–167.[CrossRef][Medline]
  21. Ferguson MK, Lehman AG. Sleeve lobectomy or pneumonectomy: Optimal management strategy using decision analysis techniques. Ann Thorac Surg 2003;76:1782–1788.[Abstract/Free Full Text]
  22. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615–622; discussion 622–623.[Abstract/Free Full Text]
  23. Kodama K, Doi O, Higashiyama M et al. Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: A single-institution study. J Thorac Cardiovasc Surg 1997;114:347–353.[Abstract/Free Full Text]
  24. El-Sherif A, Gooding WE, Santos R et al. Outcomes of sublobar resection versus lobectomy for stage I non-small cell lung cancer: A 13-year analysis. Ann Thorac Surg 2006;82:408–415; discussion 415–416.[Abstract/Free Full Text]
  25. Warren WH, Faber LP. Segmentectomy versus lobectomy in patients with stage I pulmonary carcinoma. Five-year survival and patterns of intrathoracic recurrence. J Thorac Cardiovasc Surg 1994;107:1087–1093; discussion 1093–1094.[Abstract/Free Full Text]
  26. Lederle FA. Lobectomy versus limited resection in T1 N0 lung cancer. Ann Thorac Surg 1996;62:1249–1250.[Free Full Text]
  27. Nakamura H, Kawasaki N, Taguchi M et al. Survival following lobectomy vs limited resection for stage I lung cancer: A meta-analysis. Br J Cancer 2005;92:1033–1037.[CrossRef][Medline]
  28. McKenna RJ Jr, Houck WV. New approaches to the minimally invasive treatment of lung cancer. Curr Opin Pulm Med 2005;11:282–286.[CrossRef][Medline]
  29. Sugi K, Kaneda Y, Esato K. Video-assisted thoracoscopic lobectomy achieves a satisfactory long-term prognosis in patients with clinical stage IA lung cancer. World J Surg 2000;24:27–30; discussion 30–31.[CrossRef][Medline]
  30. Kirby TJ, Mack MJ, Landreneau RJ et al. Lobectomy–video-assisted thoracic surgery versus muscle-sparing thoracotomy. A randomized trial. J Thorac Cardiovasc Surg 1995;109:997–1001; discussion 1001–1002.[Abstract]
  31. Atkins BZ, Harpole DH Jr, Mangum JH et al. Pulmonary segmentectomy by thoracotomy or thoracoscopy: Reduced hospital length of stay with a minimally-invasive approach. Ann Thorac Surg 2007;84:1107–1112; discussion 1112–1113.[Abstract/Free Full Text]
  32. Swanson SJ, Batirel HF. Video-assisted thoracic surgery (VATS) resection for lung cancer. Surg Clin North Am 2002;82:541–559.[CrossRef][Medline]
  33. Ali MK, Ewer MS, Atallah MR et al. Regional and overall pulmonary function changes in lung cancer. Correlations with tumor stage, extent of pulmonary resection, and patient survival. J Thorac Cardiovasc Surg 1983;86:1–8.[Abstract]
  34. Nakahara K, Monden Y, Ohno K et al. A method for predicting postoperative lung function and its relation to postoperative complications in patients with lung cancer. Ann Thorac Surg 1985;39:260–265.[Abstract]
  35. Win T, Groves AM, Ritchie AJ et al. The effect of lung resection on pulmonary function and exercise capacity in lung cancer patients. Respir Care 2007;52:720–726.[Medline]
  36. Sarna L, Evangelista L, Tashkin D et al. Impact of respiratory symptoms and pulmonary function on quality of life of long-term survivors of non-small cell lung cancer. Chest 2004;125:439–445.[CrossRef][Medline]
  37. Handy JR Jr, Asaph JW, Skokan L et al. What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest 2002;122:21–30.[CrossRef][Medline]
  38. Karmakar MK, Ho AM. Postthoracotomy pain syndrome. Thorac Surg Clin 2004;14:345–352.[CrossRef][Medline]
  39. Rogers ML, Duffy JP. Surgical aspects of chronic post-thoracotomy pain. Eur J Cardiothorac Surg 2000;18:711–716.[Abstract/Free Full Text]
  40. Little AG, Rusch VW, Bonner JA et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg 2005;80:2051–2056.[Abstract/Free Full Text]
  41. Jaklitsch MT, Mery CM, Audisio RA. The use of surgery to treat lung cancer in elderly patients. Lancet Oncol 2003;4:463–471.[CrossRef][Medline]
  42. Damhuis R, Coonar A, Plaisier P et al. A case-mix model for monitoring of postoperative mortality after surgery for lung cancer. Lung Cancer 2006;51:123–129.[CrossRef][Medline]
  43. Qiao X, Tullgren O, Lax I et al. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41:1–11.[Medline]
  44. Mehta M, Scrimger R, Mackie R et al. A new approach to dose escalation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001;49:23–33.[CrossRef][Medline]
  45. Kavanagh BD, McGarry RC, Timmerman RD. Extracranial radiosurgery (stereotactic body radiation therapy) for oligometastases. Semin Radiat Oncol 2006;16:77–84.[CrossRef][Medline]
  46. Fowler JF, Tome WA, Fenwick JD et al. A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys 2004;60:1241–1256.[CrossRef][Medline]
  47. McGarry RC, Papiez L, Williams M et al. Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study. Int J Radiat Oncol Biol Phys 2005;63:1010–1015.[CrossRef][Medline]
  48. Nagata Y, Takayama K, Matsuo Y et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2005;63:1427–1431.[CrossRef][Medline]
  49. Onishi H, Araki T, Shirato H et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: Clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004;101:1623–1631.[CrossRef][Medline]
  50. Baumann P, Nyman J, Lax I et al. Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries. Acta Oncol 2006;45:787–795.[CrossRef][Medline]
  51. Lagerwaard FJ, Haasbeek CJ, Slotman BJ et al. Clinical results and toxicity after 4-dimensional stereotactic radiotherapy for early stage non-small cell lung cancer (NSCLC): B5–04. J Thorac Oncol 2007;2(suppl 4):S348.
  52. Onishi H, Shirato H, Nagata Y et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: Updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2007;2(suppl 3):S94–S100.
  53. Strand TE, Rostad H, Moller B et al. Survival after resection for primary lung cancer: A population based study of 3211 resected patients. Thorax 2006;61:710–715.[Abstract/Free Full Text]
  54. Bradley J. Radiographic response and clinical toxicity following SBRT for stage I lung cancer. J Thorac Oncol 2007;2(suppl 3):S118–S124.
  55. Timmerman R, McGarry R, Yiannoutsos C et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:4833–4839.[Abstract/Free Full Text]
  56. Wulf J, Baier K, Mueller G et al. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol 2005;77:83–87.[CrossRef][Medline]
  57. Lagerwaard FJ, van der Geld Y, Slotman BJ et al. 1009: Quality of life after stereotactic radiotherapy for medically inoperable stage I lung cancer. Int J Radiat Oncol Biol Phys 2006;66(suppl 1):S133–S134.
  58. Ohashi T, Takeda A, Shigematsu N et al. Differences in pulmonary function before vs. 1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors. Int J Radiat Oncol Biol Phys 2005;62:1003–1008.[Medline]
  59. Henderson MA, McGarry RC, Yiannoutsos C et al. 162: Stereotactic body radiotherapy for early stage non-small-cell lung cancer in patients with very poor pulmonary function. Int J Radiat Oncol Biol Phys 2006;66(suppl 1):S91.
  60. Higgins H, Berger DL. RFA for liver tumors: Does it really work? The Oncologist 2006;11:801–808.[Abstract/Free Full Text]
  61. Lencioni R, Crocetti L, Cioni R et al. Radiofrequency ablation of lung malignancies: Where do we stand? Cardiovasc Intervent Radiol 2004;27:581–590.[CrossRef][Medline]
  62. Iguchi T, Hiraki T, Gobara H et al. Percutaneous radiofrequency ablation of lung tumors close to the heart or aorta: Evaluation of safety and effectiveness. J Vasc Interv Radiol 2007;18:733–740.[CrossRef][Medline]
  63. Abbas G, Schuchert MJ, Pennathur A et al. Ablative treatments for lung tumors: Radiofrequency ablation, stereotactic radiosurgery, and microwave ablation. Thorac Surg Clin 2007;17:261–271.[CrossRef][Medline]
  64. Simon CJ, Dupuy DE, Dipetrillo TA et al. Pulmonary radiofrequency ablation: Long-term safety and efficacy in 153 patients. Radiology 2007;243:268–275.[Abstract/Free Full Text]
  65. de Baere T, Palussiere J, Auperin A et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: Prospective evaluation. Radiology 2006;240:587–596.[Abstract/Free Full Text]
  66. Hiraki T, Tajiri N, Mimura H et al. Pneumothorax, pleural effusion, and chest tube placement after radiofrequency ablation of lung tumors: Incidence and risk factors. Radiology 2006;241:275–283.[Abstract/Free Full Text]
  67. Yan TD, King J, Sjarif A et al. Treatment failure after percutaneous radiofrequency ablation for nonsurgical candidates with pulmonary metastases from colorectal carcinoma. Ann Surg Oncol 2007;14:1718–1726.[CrossRef][Medline]
  68. FDA Public Health Notification. Deaths Reported Following Radio Frequency Ablation of Lung Tumors. Publication Date: December 11, 2007. Available at http://www.fda.gov/cdrh/safety/121107-rfablation.html. Accessed December 21, 2007.
  69. van Iersel CA, de Koning HJ, Draisma G et al. Risk-based selection from the general population in a screening trial: Selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer 2007;120:868–874.[CrossRef][Medline]
  70. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604–1608.[Abstract]
  71. Sawada S, Yamashita M, Komori E et al. Evaluation of resected tumors that were not diagnosed histologically but were suspected of lung cancer preoperatively: PD1–3-5. J Thorac Oncol 2007;2(suppl 4):S422.
  72. Swensen SJ, Silverstein MD, Ilstrup DM et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–855.[Abstract/Free Full Text]
  73. Herder GJ, van Tinteren H, Golding RP et al. Clinical prediction model to characterize pulmonary nodules: Validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest 2005;128:2490–2496.[CrossRef][Medline]
  74. van Tinteren H, Hoekstra OS, Smit EF et al. Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: The PLUS multicentre randomised trial. Lancet 2002;359:1388–1393.[CrossRef][Medline]
  75. Spira A, Beane JE, Shah V et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007;13:361–366.[CrossRef][Medline]
  76. Kikuchi T, Carbone DP. Proteomics analysis in lung cancer: Challenges and opportunities. Respirology 2007;12:22–28.[CrossRef][Medline]
  77. McWilliams A, Mayo J, MacDonald S et al. Lung cancer screening: A different paradigm. Am J Respir Crit Care Med 2003;168:1167–1173.[Abstract/Free Full Text]
  78. Zeng H, McWilliams A, Lam S. Optical spectroscopy and imaging for early lung cancer detection: A review. Photodiagn Photodyn Ther 2004;1:111–122.
  79. Vergnon JM, Huber RM, Moghissi K. Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers. Eur Respir J 2006;28:200–218.[Abstract/Free Full Text]
  80. Taulelle M, Chauvet B, Vincent P et al. High dose rate endobronchial brachytherapy: Results and complications in 189 patients. Eur Respir J 1998;11:162–168.[Abstract/Free Full Text]
  81. McCaughan JS Jr, Williams TE. Photodynamic therapy for endobronchial malignant disease: A prospective fourteen-year study. J Thorac Cardiovasc Surg 1997;114:940–946.[Abstract/Free Full Text]
  82. Pignon JP, Tribodet H, Scagliotti GV et al. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. J Clin Oncol 2006;24;(18) (suppl):366S.
  83. Chen HY, Yu SL, Chen CH et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 2007;356:11–20.[Abstract/Free Full Text]
  84. Potti A, Mukherjee S, Petersen R et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570–580.[Abstract/Free Full Text]
  85. Ohtsuka T, Nomori H, Watanabe K et al. Prognostic significance of [(18)F]fluorodeoxyglucose uptake on positron emission tomography in patients with pathologic stage I lung adenocarcinoma. Cancer 2006;107:2468–2473.[Medline]
  86. Olaussen KA, Dunant A, Fouret P et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983–991.[Abstract/Free Full Text]
  87. Rusch VW, Crowley J, Giroux DJ et al. The IASLC Lung Cancer Staging Project: Proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:603–612.[CrossRef][Medline]
  88. Postmus PE, Brambilla E, Chansky K et al. The IASLC Lung Cancer Staging Project: Proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007;2:686–693.[CrossRef][Medline]
  89. Thomas P, Doddoli C, Thirion X et al. Stage I non-small cell lung cancer: A pragmatic approach to prognosis after complete resection. Ann Thorac Surg 2002;73:1065–1070.[Abstract/Free Full Text]
  90. Ludwig C, Stoelben E, Olschewski M et al. Comparison of morbidity, 30-day mortality, and long-term survival after pneumonectomy and sleeve lobectomy for non-small cell lung carcinoma. Ann Thorac Surg 2005;79:968–973.[Abstract/Free Full Text]
  91. Harpole DH Jr, DeCamp MM Jr, Daley J et al. Prognostic models of thirty-day mortality and morbidity after major pulmonary resection. J Thorac Cardiovasc Surg 1999;117:969–979.[Abstract/Free Full Text]
  92. Reilly JJ Jr. Evidence-based preoperative evaluation of candidates for thoracotomy. Chest 1999;116;(6) (suppl):474S–476S.[CrossRef][Medline]
  93. Benzo R, Kelley GA, Recchi L et al. Complications of lung resection and exercise capacity: A meta-analysis. Respir Med 2007;101:1790–1797.[CrossRef][Medline]
  94. Burke JR, Duarte IG, Thourani VH et al. Preoperative risk assessment for marginal patients requiring pulmonary resection. Ann Thorac Surg 2003;76:1767–1773.[Abstract/Free Full Text]
  95. Iizasa T, Suzuki M, Yasufuku K et al. Preoperative pulmonary function as a prognostic factor for stage I non-small cell lung carcinoma. Ann Thorac Surg 2004;77:1896–1902; discussion 1902–1903.[Abstract/Free Full Text]
  96. Nyman J, Johansson KA, Hulten U. Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer—mature results for medically inoperable patients. Lung Cancer 2006;51:97–103.[CrossRef][Medline]
  97. Uematsu M, Shioda A, Suda A et al. Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small cell lung cancer: A 5-year experience. Int J Radiat Oncol Biol Phys 2001;51:666–670.[CrossRef][Medline]
  98. Xia T, Li H, Sun Q et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;66:117–125.[CrossRef][Medline]
  99. Sakurai J, Hiraki T, Mukai T et al. Intractable pneumothorax due to bronchopleural fistula after radiofrequency ablation of lung tumors. J Vasc Interv Radiol 2007;18:141–145.[CrossRef][Medline]
  100. Hiraki T, Sakurai J, Tsuda T et al. Risk factors for local progression after percutaneous radiofrequency ablation of lung tumors: Evaluation based on a preliminary review of 342 tumors. Cancer 2006;107:2873–2880.[Medline]
  101. Yamagami T, Kato T, Hirota T et al. Pneumothorax as a complication of percutaneous radiofrequency ablation for lung neoplasms. J Vasc Interv Radiol 2006;17:1625–1629.[CrossRef][Medline]
  102. Kang S, Luo R, Liao W et al. Single group study to evaluate the feasibility and complications of radiofrequency ablation and usefulness of post treatment positron emission tomography in lung tumours. World J Surg Oncol 2004;2:30.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
R. J. Landreneau
Invited Commentary
Ann. Thorac. Surg., April 1, 2009; 87(4): 1028 - 1029.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haasbeek, C. J.A.
Right arrow Articles by Lagerwaard, F. J.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Haasbeek, C. J.A.
Right arrow Articles by Lagerwaard, F. J.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS