Diagnosis and multimodality management of stage III non-small cell lung cancer Review Article

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1 Cancer Therapy Vol 6, page 81 Cancer Therapy Vol 6, 81-94, 2008 Diagnosis and multimodality management of stage III non-small cell lung cancer Review Article Kevin Sullivan, Zujun Li, John Rescigno, Michael Fanucchi* St. Vincent s Comprehensive Cancer Center and New York Medical College, New York, NY *Correspondence: Michael Fanucchi, MD, St. Vincent's Comprehensive Cancer Center, 325 West 15th Street, New York, NY 10011, USA; Tel: (212) ; Fax: (212) ; Mfanucchi@aptiumoncology.com Key words: Diagnosis, staging, Treatment, N2 disease, Preoperative chemotherapy, Preoperative chemoradiotherapy, radiotherapy, neoadjuvant therapy, Adjuvant therapy, Superior sulcus tumors, Satellite nodules, Mediastinal invasion, Targeted therapy, Immunotherapy, Prophylactic cranial irradiation Abbreviations: 3-dimensional, (3D); Adjuvant Navelbine International Trialist Association, (ANITA); American Society of Clinical Oncology, (ASCO); Cancer and Leukemia Group B, (CALGB); Cancer Care Ontario, (CCO); central nervous system, (CNS); computed tomography, (CT); disease free survival, (DFS); Eastern Cooperative Oncology Group, (ECOG); Electromagnetic navigation bronchoscopy, (ENB); endobronchial ultrasound-guided transbronchial needle aspiration, (EBUS-TBNA); epidermal growth factor receptor, (EGFR); European Organization for Research and Treatment of Cancer, (EORTC); European Society of Thoracic Surgeons, (ESTS); fine needle aspiration, (FNA); Fluoro-Deoxy-Glucose, (FDG); granulocyte macrophage colony stimulating factor, (GM-CSF); hazard ratio, (HR); hyperfractionated RT, (HART); intensity modulated radiotherapy, (IMRT); International Adjuvant Lung Cancer Trial, (IALT); International Association for the Study of Lung Cancer, (IASLC); International Staging System, (ISS); magnetic resonance imaging, (MRI); median survival, (MS); National Comprehensive Cancer Network, (NCCN); Non-Small Cell lung cancer, (NSCLC); overall survival, (OS); performance status, (PS); Positron emission tomography, (PET); progression free survival, (PFS); Prophylactic cranial irradiation, (PCI); Radiation Therapy Oncology Group, (RTOG); radiation therapy, (RT); response rate, (RR); Southwest Oncology Group, (SWOG); time to progression, (TTP); tumor-node-metastasis, (TNM); video-assisted thoracoscopic surgery, (VATS) Received: 31 December 2007; Revised: 30 January 2008 Accepted: 1 February 2008; electronically published: February 2008 Summary Stage III non-small cell lung cancer (NSCLC) encompasses a heterogeneous patient population with locoregionally advanced disease. The multimodality management of patients with this stage of disease is reviewed, including diagnosis, staging and treatment. Evidenced-based treatment approaches are emphasized including chemotherapy and radiotherapy in the neoadjuvant, adjuvant and definitive setting. The role of surgery in select patients is discussed. I. Introduction In the United States, lung cancer is the leading cause of cancer death in both men and women. An estimated 213,380 new cases of lung cancer were diagnosed in 2007, with 68,280 patients having stage IIIA/B disease (Jemal et al, 2007). Non-Small Cell lung cancer (NSCLC) represents about 80% of all histological types of lung cancer and includes adenocarcinoma (including its subset, bronchioloalveolar carcinoma), squamous cell (epidermoid) carcinoma, and large cell carcinoma (Fraire, 1996; Travis et al, 2004). The International Staging System (ISS) is the most commonly used staging system for NSCLC (Mountain, 1997). Although there is a proposal to modify the TNM staging of lung cancer under consideration by the International Association for the Study of Lung Cancer (IASLC) (Rami-Porta et al, 2007), the ISS, which was last revised in 1997, is still in current use. Stage III NSCLC is defined as locoregionally advanced disease, due to involvement of mediastinal lymph nodes, involvement or invasion of extrapulmonary structures, or the presence of a malignant pleural or pericardial effusion, without evidence of distant metastatic disease. Stage III NSCLC is subdivided into Stage IIIA and IIIB disease. Stage IIIA disease is a T1 or T2 tumor with involvement of ipsilateral mediastinal lymph nodes (N2), or a T3 lesion with hilar (N1) or mediastinal (N2) lymph node involvement. Stage IIIA patients are further clinically subdivided into bulky and non-bulky disease. Bulky disease includes lymph nodes which are >2cm in diameter as measured by 81

2 Sullivan et al: Diagnosis and multimodality management of stage III non-small cell lung cancer computed tomography (CT), or conglomeration of multiple smaller lymph nodes (Robinson et al, 2003). Patients with non-bulky N2 disease may be rendered disease free by surgical resection, whereas patients with bulky disease are generally inoperable due to extent of nodal disease. Stage IIIB disease is based upon the presence of a T4 tumor, or involvement of supraclavicular lymph nodes or contralateral mediastinal or hilar lymph nodes (N3). Stage IIIB disease due to the presence of a malignant pleural or pericardial effusion is managed primarily with chemotherapy alone and will not be discussed here. II. Diagnosis and staging evaluation The diagnosis of NSCLC requires a tissue biopsy to identify the histopathologic subtype as well as proper staging of the tumor, according to tumor-node-metastasis (TNM) descriptions (Fossella et al, 2003). Tissue specimens may be obtained via bronchial washings, bronchial brushings, fine needle aspiration (FNA) biopsy, core needle biopsy, endobronchial biopsy, or transbronchial biopsy. Electromagnetic navigation bronchoscopy (ENB) can be used to biopsy peripheral lesions with a higher accuracy and lower risk of pneumothorax than CT-guided percutaneous FNA biopsy (Eberhardt et al, 2007). Occasionally, mediastinoscopy, parasternal mediastinotomy, video-assisted thoracoscopic surgery (VATS) or open thoracotomy is required to obtain tissue. CT scanning of the chest and upper abdomen is often used for the initial assessment of disease stage, but there are limitations in the evaluation of hilar and mediastinal lymph node involvement (Patterson et al, 1987). Node positivity is based on the size of the lymph nodes in CT scanning assessment. Because of this, small metastases that do not cause nodal enlargement will be missed. A 16% false negative result in metastases to lymph nodes that were found to be normal in size on CT scanning has been reported, with subsequent pathologic confirmation of N2 or N3 disease (Arita et al, 1995). Chest CT scans have a sensitivity and specificity of 69% and 71%, respectively, for identifying N2 disease (Dillemans et al, 1994). Another study found a sensitivity of 40-65% and specificity of 45-90% for CT scan detection of mediastinal lymph node involvement, depending on the clinical scenario (McLoud et al, 1992). An additional study reported a positive predictive value of 43% and negative predictive value of 92% for chest CT scans identifying mediastinal lymph node involvement (Seely et al, 1993). Currently, mediastinoscopy is the gold standard for the pre-operative evaluation of mediastinal lymph nodes, and is appropriate to confirm node positivity in those with a positive CT scan. Positron emission tomography (PET) scans detect tumor physiology rather than tumor anatomy, and may therefore be more sensitive than CT scans for clinical staging (Kerr et al, 1992). PET imaging scans have been useful in providing more accurate clinical staging and for evaluating the extent of disease. PET scans have been found to be 78% sensitive and 81% specific, with a negative predictive value of 89% when used to stage the mediastinal lymph nodes (Chin et al, 1995). PET scan was compared with CT scan for accuracy in identifying N2 and N3 disease, and the PET scan was found to be more sensitive (81%) versus CT scan (76%) (Kerstine et al, 1998). The most accurate method of clinically staging the mediastinal lymph nodes is integrated PET/CT (Lardinois et al, 2003). Integrated PET/CT provided additional information in 41% of patients beyond that provided by visual correlation of PET and CT. Patients that have a negative PET/CT evaluation of the mediastinal lymph nodes may proceed to surgical resection without preoperative mediastinoscopy (Vansteenkiste 2006). The European Society of Thoracic Surgeons (ESTS) recommends invasive staging despite a negative PET/CT evaluation of mediastinal lymph nodes in cases of central tumors, Fluoro-Deoxy-Glucose (FDG)-avid hilar lymph nodes, low FDG uptake of the primary tumor and lymph nodes greater than or equal to 16 millimeters (mm) on CT scan (De Leyn et al, 2007). Most clinicians recommend pathologic evaluation of FDG-avid mediastinal lymph nodes, particularly for patients with non-bulky disease by CT. Endoscopic ultrasound imaging permits rapid and accurate identification and subsequent needle biopsy of mediastinal lymph nodes. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have been useful for lymph node staging of lung cancer (Vilmann et al, 2005). EBUS- TBNA was compared with CT and PET for evaluating mediastinal and hilar nodes in patients with lung cancer and had a sensitivity and specificity of 92% and 100% respectively (Yasufuku et al, 2006). Transesophageal ultrasound-guided lymph node biopsy was compared to surgical mediastinoscopy and was shown to be highly sensitive for the detection of metastatic nodes, especially in the paratracheal and subcarinal regions (Larsen et al, 2005). Endoscopic ultrasound with FNA is being increasingly used in lung cancer staging, and may decrease the need for mediastinoscopy. Lung cancer causes brain metastases in 18-64% of patients during the course of their illness (Lassman, 2003). At presentation, 10% of all patients with NSCLC have central nervous system (CNS) involvement, with up to 20% of patients with adenocarcinoma having occult brain metastases (Newman, 1974; White et al, 1981). Brain magnetic resonance imaging (MRI) to evaluate for asymptomatic brain metastases is recommended in those patients with clinical stage III disease (Mayr et al, 1995), as outlined in the National Comprehensive Cancer Network (NCCN) guidelines (NCCN Clinical Practice Guidelines in Oncology, 2008). III. Treatment The treatment plan depends on whether the patient was diagnosed with stage III disease before or after surgical resection. Patients with clinical stage I or II NSCLC that undergo surgical resection, may then be reclassified as stage III based on metastases in mediastinal lymph nodes in the final pathology specimen. These patients are recommended to receive adjuvant 82

3 Cancer Therapy Vol 6, page 83 chemotherapy to reduce the risk of recurrence (see Adjuvant Therapy in Resected Patients discussed below). Patients who are confirmed to have mediastinal lymph node involvement prior to resection are recommended to have either preoperative therapy or definitive chemotherapy and radiation therapy (RT) without surgical resection. A. Clinically evident but potentially resectable N2 disease For patients with non-bulky mediastinal lymph node involvement and T1-3 primary tumors, a combined modality treatment approach is recommended for management. Treatment options include preoperative induction therapy with chemotherapy or chemoradiotherapy; or definitive treatment with chemotherapy and radiotherapy given in a sequential fashion or concurrently. As per the NCCN guidelines, induction chemotherapy with or without RT could be considered for patients with T1-2 N2 disease. Definitive concurrent chemoradiotherapy could also be considered for this type of lesion, and is recommended for patients with T3 N2 disease. Additionally, the NCCN recommends the consideration of surgical resection if there has been an excellent response to the induction/definitive treatment (NCCN Clinical Practice Guidelines in Oncology, 2008). 1. Preoperative chemotherapy vs. preoperative chemoradiotherapy It is unknown whether neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy. This issue is being addressed by the Swiss Group for Clinical Cancer Research conducting a phase III randomized trial of preoperative cisplatin and docetaxel chemotherapy versus chemoradiotherapy with the same agents followed by surgical resection in patients with stage IIIA NSCLC. Radiation Therapy Oncology Group (RTOG) trial 0412 and Southwest Oncology Group (SWOG) trial S0332 is a phase III randomized trial in favorable prognosis patients with stage IIIA NSCLC comparing preoperative chemotherapy (with cisplatin and docetaxel) to preoperative concurrent chemoradiotherapy (50.4 Gy thoracic RT with the same chemotherapy agents). Both arms receive postoperative chemotherapy with docetaxel. This study closed prematurely due to slow accrual. Several small phase II and III studies substantiate the benefit of preoperative chemotherapy. Skarin and colleagues reported a median survival of 32 months with 1-year survival of 75% in 41 patients receiving neoadjuvant cyclophosphamide, adriamycin, and cisplatin chemotherapy followed by RT and subsequent resection (Skarin et al, 1989). Pass and colleagues reported a prospective, randomized trial in 27 patients with stage IIIA (N2) NSCLC comparing preoperative etoposide-platinum chemotherapy followed by surgery and postoperative chemotherapy with surgery followed by postoperative mediastinal RT (Pass et al, 1992). A trend toward increased survival was reported for the preoperative chemotherapy group (28.7 months vs months, p=0.095). Roth and colleagues performed a prospective, randomized study of 60 patients with clinical stage IIIA NSCLC comparing perioperative chemotherapy (with cisplatin, cyclophosphamide and etoposide) vs. surgery alone (Roth et al, 1994). The perioperative chemotherapy group received 3 cycles of chemotherapy followed by surgical resection. Three additional cycles of postoperative chemotherapy were given to those patients who responded to the preoperative treatment. The patients in the chemotherapy group had a median survival of 64 months compared with 11 months in the surgery alone group (p<0.008). Two and three year survival rates in the perioperative chemotherapy group were 60% and 56% vs. 25% and 15% respectively in the surgery along group. Rosell and colleagues studied 60 patients with stage IIIA NSCLC randomly assigned to receive surgery alone vs. 3 cycles of chemotherapy with cisplatin, ifosfamide and mitomycin followed by surgery (Rosell et al, 1994). All patients had postoperative mediastinal RT. Median survival was 26 months in the chemotherapy group vs. 8 months in the surgery alone group (p<0.001). In the Spanish Lung Cancer Group Trial 9901, Garrido and colleagues reported survival results for 129 patients with stage IIIA (N2) and IIIB (T4 N0-1) NSCLC receiving induction chemotherapy with three cycles of cisplatin, gemcitabine and docetaxel followed by surgery in responding patients (Garrido et al, 2007). The patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. In this study 50.7% were stage IIIA and 49.3% were stage IIIB. Seventy percent of the patients underwent surgery, with 68.9% of the patients undergoing complete resection. Median overall survival (OS) was 15.9 months, 3-year and 5-year survival rate was 36.8% and 21.1% respectively, with no significant survival differences between stage IIIA and IIIB patients. Median survival time was 48.5 months for 62 completely resected patients, 12.9 months for 13 incompletely resected patients and 16.8 months for 15 nonresected patients (p=0.005). Survival rates at 3 and 5 years were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients. 2. Surgical resection vs. radiotherapy following neoadjuvant therapy The role of surgical resection, in comparison to RT, following induction therapy in patients with stage IIIA disease is unclear. Two large randomized phase III trials have not found a survival benefit for surgery in comparison to RT following chemotherapy or for surgery following concurrent chemoradiotherapy. Chemoradiotherapy in this setting may be sufficient. The European Organization for Research and Treatment of Cancer (EORTC) study examined the issue of radiotherapy versus surgical resection following induction chemotherapy in patients with clinical stage IIIA-N2 NSCLC (van Meerbeeck et al, 2007). In this study, 579 patients received induction chemotherapy with three cycles of platinum-based chemotherapy. Following chemotherapy, 332 patients with at least stable disease were randomized to receive definitive RT [ Gray (Gy) to the primary tumor and involved mediastinum with 83

4 Sullivan et al: Diagnosis and multimodality management of stage III non-small cell lung cancer Gy to the uninvolved mediastinum] vs. surgical resection. Surgical resection did not improve OS or progression free survival (PFS) compared with RT. The Intergroup 0139 trial evaluated 429 patients with stage IIIA NSCLC that were treated initially with concurrent RT (45 Gy) plus chemotherapy with cisplatin (50 mg/m2 on days 1, 8, 29, and 35) plus etoposide (50 mg/m2 on days 1 to 5, and 29 to 33); 396 patients with at least stable disease were then randomized to surgical resection or a continuation of RT (to 61 Gy) (Albain et al, 2005). Two additional cycles of chemotherapy were given to both groups. A planned interim analysis, reported in abstract form, revealed that surgery was associated with a significant increase in five-year PFS (22 vs. 11 percent), but only a trend toward better OS (27 vs. 20 percent, p=0.10) due to increased post-operative deaths in patients in the surgery arm who required pneumonectomy. Over one-fourth of the patients who required pneumonectomy (n=54) died within 30 days post-operatively, but the survival curves crossed at approximately 18 months follow-up, and the hazard ratio for death was 0.87 for those randomized to surgery (p=0.24). Local relapse was significantly less in patients who underwent surgery (10% vs. 22%, p=0.002). Five-year survival for patients downstaged to node negative was 41% as compared to 24% for those with residual nodal disease. Approximately 13% suffered isolated brain metastases and the overall distant metastases rate was 40%. Table 1 summarizes the OS data comparing surgery with RT. These data suggest that surgery does not have an established role in the treatment of patients with clinical N2 disease. However, surgery may have a role after preoperative chemoradiation in patients who do not require pneumonectomy, particularly if there has been a response to the preoperative therapy. Additionally, there may be a role for surgery in patients with small volume N2 disease who receive preoperative chemotherapy or preoperative chemoradiotherapy. There is not a consensus from the NCCN in this regard 27. Re-staging should be considered following neoadjuvant treatment, but it is unclear if complete elimination of N2 disease is a requirement to benefit from surgery. B. Unresectable Stage III NSCLC In patients with unresectable stage III NSCLC due to T4 primary tumors, bulky N2 disease, or N3 disease, chemotherapy and RT have been combined in various algorithms in an effort to treat both locoregional and micrometastatic disease. Table 2 summarizes the median and 5-year survival rates comparing RT alone, sequential chemoradiotherapy and concurrent chemoradiotherapy in select studies. Table 1. OS at 5 years comparing surgery with radiotherapy after induction therapy. Study Randomized Surgical Radiotherapy P value Reference patients resection EORTC % 14% 0.60 van Meerbeeck et al, 2007 Intergroup % 20% 0.10 Albain et al, 2005 Table 2. Outcomes of sequential and concurrent chemoradiotherapy compared with radiotherapy alone. *NA = Not Available. Study CALGB 8433 Randomized patients Treatment Median survival (mos) Radiotherapy Sequential Chemoradiotherapy Radiotherapy Intergroup 432 Sequential Chemoradiotherapy year survival rate (%) Radiotherapy 10 3 French 353 Sequential Chemoradiotherapy 12 6 Radiotherapy NA* 2 (3-year) EORTC 331 Concurrent Chemoradiotherapy NA* 16 (3-year) Radiotherapy 8 2 (3-year) Cakir et al 176 Concurrent Chemoradiotherapy (3-year) P value Reference Dillman et al, 1996 Sause et al, 2000 Le Chevalier et al, 1994 Schaake- Koning et al, 1992 Cakir, 2004 Dillman et al, 1996 Sause et al, 2000 Le Chevalier et al, 1994 Schaake- Koning et al,

5 Cancer Therapy Vol 6, page Radiotherapy techniques and definitive radiotherapy Definitive RT is a treatment option for patients with stage III NSCLC who are not candidates for combined modality therapy due to poor PS or medical conditions. The RTOG was designed to assess optimal dose of radiotherapy for patients with locally advanced disease (Perez et al, 1987). Local control and 2 year survival were better with 60 Gy in 6 weeks compared with lower doses. RTOG tested whether improved results could be obtained with higher RT doses and twice-daily fractionation (hyperfractioned accelerated RT-HART), a technique that could potentially spare normal tissues from late toxicity (Cox et al, 1990). In this study, 840 patients were treated with 1.2 Gy twice daily with 4-6 hours between fractions to total doses ranging from Gy. The best results were obtained with HART of 69.6 Gy at 1.2 Gy twice daily over 6! weeks. In patients with N2 disease, weight loss of 5% or less, and good performance status, 3 year survival of 20% was achieved with HART as compared with 7% survival for similar patients treated on earlier RTOG trials of standard fractionation. Saunders and colleagues conducted a phase III randomized trial comparing 60 Gy in 6 weeks and 54 Gy given at 1.5 Gy three times daily (six hour interfraction interval), seven days per week (continuous hyperfractionated accelerated radiotherapy-chart) (Saunders et al, 1999). Three year survival was 20% with CHART vs. 13% with standard RT, at the expense of more moderate and severe acute dysphagia. This trial validated the concept of accelerated hyperfractionation as safe and appeared to be more effective than standard fractionation when RT is used as single modality therapy, however this was the only trial that showed improved results and has not been confirmed. Efforts have also been made to increase the efficacy of RT through dose-escalation, which is made possible by decreasing the volume of normal tissue in the radiation field. The use of 3-dimensional (3D)-conformal techniques, which are now standard, has made possible a decrease in normal tissues receiving high doses. It has also raised the question of whether reductions in radiation target volume by avoidance of elective nodal irradiation may be appropriate. Since most locoregional failures occur at the sites of initial gross disease, exclusion of elective nodal irradiation (so-called involved-field radiotherapy) has become increasingly utilized. A recent study by Rosenszweig and colleagues found only 6.1 % isolated failure at nodes that were outside the high dose radiation volume in 524 patients treated with 3D conformal radiotherapy (Rosenzweig et al, 2007). This is, however, at odds with surgical data suggesting high rates of occult involvement of mediastinal nodes even with small primary tumors. A therapeutic benefit from lower dose incidental radiation of nearby nodal stations when multiple-field 3D dose-escalated conformal techniques are used in conjunction with chemotherapy may effectively treat subclinical nodal disease. However, competing risks of progression at distant metastatic sites and death from both local recurrence and distant metastases are likely to be the primary reasons few patients are reported to have progression at nodes not clinically involved at the time of diagnosis. In this regard, potential improvements in the ability of radiation to eradicate known locoregional sites of disease through dose-escalation, and perhaps looking forward, improved chemosensitization and more effective systemic treatment for occult distant disease, will force a re-evaluation of the role of elective nodal irradiation. 3-D conformal therapy techniques allow the development of complex multiple field radiotherapy plans that decrease the amount of normal tissue exposed to high doses. The feasibility of delivering much higher doses of radiotherapy with modern techniques has been demonstrated in phase I and II studies. A dose escalation study reported by Haymen and colleagues involved 104 patients, most of whom had stage III disease (Hayman et al, 2001). The dose escalation schema depended on the amount of normal lung in the radiation field based on the 3-D conformal therapy plan. For patients with the greatest quintile of normal lung exposed to radiation, a maximum tolerated dose of 65.1 Gy at 2.1 Gy per day was reached; however, for the other four groups, continued escalation beyond 75.6 Gy and up to more than 100 Gy in the two quintiles with the lowest normal lung exposure was associated with acceptable toxicity. The RTOG conducted a phase I/II dose-escalation trial that incorporated 3D conformal therapy in 179 patients (Bradley et al, 2005). Concurrent chemotherapy was not given. Dose escalation was based on the volume of lung exposed to 20 Gy, which is near the tolerance dose of normal lung and has been shown to correlate with pneumonitis risk. Radiation was delivered at 2.15 Gy per daily fraction. Doses of 77.4 Gy were found to be tolerable, and in patients with low-volume disease, doses of 83.8 Gy were feasible. Local failure at two years was 38%. However, there have been no randomized phase III trials demonstrating that dose escalation improves survival. Better delineation of the target volume can be achieved with FDG-PET, and modern RT treatment planning systems can accommodate target definition using fused PET and CT images. The target volume when PET is used has been shown to change in a significant proportion of patients as compared with CT planning alone. The RT target volume can decrease (due to the ability of PET to differentiate atelectatic lung from tumor) or increase (due to FDG uptake at mediastinal lymph nodes that were not positive by CT size criteria alone) (Lavrenkov et al, 2005; Nestle et al, 2006). In the increasingly common situation today when elective nodal irradiation is avoided, more accurate definition of involved sites of disease with PET decreases the likelihood that tumor bearing nodes will not be encompassed in the target volume. The use of techniques that account for mobility of the tumor with respiration take on greater importance when 3D conformal treatment planning is utilized. By accounting for tumor motion on an individualized basis, smaller margins can be utilized, thereby decreasing exposure to normal lung tissue. One approach to this problem is the use of respiratory gating or breath hold technique. Gating the treatment with the respiratory cycle 85

6 Sullivan et al: Diagnosis and multimodality management of stage III non-small cell lung cancer or treating with breath hold can help to reduce the planning target volume or avoid marginal miss. Another method incorporates so-called 4D imaging. Use of rapid spiral CT scanning and acquisition of multiple images during breathing allows for better definition of the target volume, so that changes in the shape and location of the tumor during the breathing cycle can be taken into account in radiation delivery. With this technique temporal changes in tumor position and anatomy are incorporated into the treatment planning process. Radiotherapy delivery that adjusts in real-time to changes in tumor and normal anatomy holds further promise to decrease the necessary tumor margin and exposure to uninvolved lung. Image guided radiotherapy may also improve the therapeutic ratio. Accurate patient set-up with the use of radiopaque markers placed in the tumor by ENB or VATS, or use of daily CT scan imaging can essentially eliminate any additional margin that might otherwise be needed for daily patient set-up variability. Adaptive radiotherapy can also be employed, in which the radiation treatment plan is modified to account for dimunition in the size of the primary tumor or mediastinal lymph nodes during the course of treatment. Use of intensity modulated radiotherapy (IMRT) is also being studied. With this technique, the intensity of the beam is varied across the two dimensions of each field, and delivery is accomplished using multiple fields at different angles. The advantage of IMRT is that high dose gradients between target and normal tissue can be generated. The primary disadvantage is that a greater volume of normal tissue gets low doses. Since the normal lung has low tolerance to even small doses, this technique has not gained general acceptance in the treatment of locally advanced non-small cell carcinoma. There are additional unsolved technological problems of moving targets and the necessity of using time-consuming respiratory gating. 2. Sequential and conurrent chemotherapy and RT vs. RT alone Clinical trials have established the superiority of sequential therapy compared with RT alone. In Cancer and Leukemia Group B (CALGB) trial 8433, cisplatinvinblastine for two cycles followed by thoracic radiotherapy to a dose of 60 Gy in 6 weeks was compared with the same radiotherapy alone in 155 randomized patients (Dillman et al, 1996). Induction chemotherapy improved median survival (13.8 months vs. 9.7 months, p=0.007), 3 year survival (23 % vs. 10 %, p=0.01) and 7 year survival (13 % vs. 6 %, p=0.01). This was the first study to demonstrate a survival benefit with the use of induction chemotherapy followed by radiotherapy for patients with good PS (ECOG 0-1) and weight loss of less than 5%. These results were confirmed in an intergroup study of 452 patients with stage III NSCLC (also with ECOG PS 0-1 and weight loss of less than 5%) randomized to the positive arm of the CALGB trial (induction vinblastine-cisplatin followed by RT) vs. the best arm of RTOG (HART alone to 69.6 Gy) vs. standard fractionation RT of 60 Gy in six weeks (Sause et al, 2000). OS was statistically superior for the patients receiving induction chemotherapy followed by RT vs. the other two arms of the study. The HART arm, although better, was not statistically superior in survival compared with the standard RT arm. Two year survival was 32 % with induction chemotherapy, 24 % for HART, and 19 % for standard RT. Three year survival was 17 %, 14 %, and 11 %, respectively. Five year survival was 8%, 6%, and 5%, respectively. A French randomized trial of 353 patients with stage III disease compared 3 cycles of induction chemotherapy with vinblastine-cisplatin-cyclophosphamide and 65 Gy thoracic RT followed by 3 more cycles of the same chemotherapy vs. RT alone to the same dose (Le Chevalier et al, 1994). Three year survival was improved with the use of induction and consolidation chemotherapy (12 % vs. 4 %, p=0.02), as was 5 year survival (6% vs. 3 %, p<0.02). This is the only study that employed systematic post-treatment bronchoscopy to evaluate locoregional control. Only 16% of patients were locally controlled at one year post-treatment, with no difference between arms, suggesting that the survival benefit afforded by chemotherapy was mainly due to its impact on occult distant metastases. A study from the EORTC reported a 3 year survival of 16 % for patients receiving chemoradiotherapy with daily concurrent cisplatin, 13 % with weekly concurrent cisplatin, and only 2 % for RT alone (p=0.009 for comparison of daily concurrent cisplatin vs. RT alone) (Schaake-Koning et al, 1992). A more recent study of 176 patients revealed improvement in 3 year survival from 2% to 10% in patients who received daily cisplatin on weeks 2 and 6 of RT (total dose 64 Gy) (Cakir, 2004). All of these trials used standard radiation doses of 55 to 60 Gy and were performed prior to the modern era of 3- D conformal therapy, which allows safe delivery of higher doses. Nonetheless, these trials, summarized in Table 2, established the use of induction chemotherapy followed by RT, or concurrent chemoradiotherapy, as superior to RT alone. 3. Concurrent chemotherapy and RT vs. sequential chemotherapy and RT Concurrent chemoradiotherapy has become the standard treatment for most unresectable patients with stage III disease based on randomized trials that have established the superiority of this approach compared with sequential therapy in patients with good PS (Table 3). To illustrate this, a Japanese study randomized 320 patients with unresectable stage III NSCLC to cisplatin, vindesine, and mitomycin concurrent with split course RT (56 Gy total dose, 10 day break) versus the same chemotherapy followed by continuous course RT to the same total dose (Furuse et al, 1999). Over 90% of the patients had an ECOG PS of 0-1. Concurrent therapy was associated with significantly better response rate (RR) of 84 vs. 66 percent, median survival (MS) of 17 vs. 13 months, and two- and five-year survival of 35 vs. 17 percent and 16 vs. 9 percent. Patients who received concurrent treatment had more myelosuppression, however there was no difference in esophagitis rates, perhaps because the concurrent radiation was given split course. Zatloukal and colleagues performed a randomized phase II trial involving

7 Cancer Therapy Vol 6, page 87 patients to compare concurrent or sequential cisplatin and vinorelbine with RT to a dose of 60 Gy (Zatloukal et al, 2004). Improved median survival of 16.6 months vs months was found with concurrent administration (p=0.02). RTOG 9410 is the largest trial assessing the value of concurrent vs. sequential therapy (Curran et al, 2003). In this trial, 610 patients with unresected stage III disease were randomized to three arms: the positive arm of the CALBG trial reported by Dillman and colleagues (induction cisplatin-vinblastine for two cycles followed by RT to 63Gy) vs. the same chemotherapy given concurrently vs. a third arm of oral etoposide and weekly cisplatin given concurrently with 69.6 Gy hyperfractionated RT (HART). Four-year survival was significantly improved with concurrent cisplatinvinblastine and standard fractionated RT vs. sequential therapy and standard fractionated RT (21% vs. 12%). The rates of acute grade 3-4 non-hematologic toxicities were higher with concurrent than sequential therapy, but late toxicities were similar (1-3% with esophagitis and 11-13% with pneumonitis). Table 4 summarizes the acute toxicities in this trial comparing concurrent vs. sequential therapy. Huber and colleagues compared concurrent chemoradiotherapy (with weekly paclitaxel) with RT alone following induction chemotherapy with carboplatin and paclitaxel in 300 patients with stage III NSCLC (Huber et al, 2006). Median time to progression (TTP) favored the chemoradiotherapy group (11.5 months vs. 6.3 months), although there was not a survival advantage observed in this trial. For patients with a compromised PS, the greater acute toxicities with concurrent therapy make sequential therapy a better choice. 4. Induction chemotherapy prior to definitive chemoradiotherapy The CALGB examined the issue of adding platinumbased induction chemotherapy prior to concurrent chemoradiotherapy in a phase III trial of 366 patients (Vokes et al, 2007). Immediate concurrent chemoradiotherapy with carboplatin AUC of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest RT was compared with induction chemotherapy with two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The addition of induction chemotherapy did not provide a survival benefit over concurrent therapy alone and was associated with an increased toxicity. This is the only prospective study comparing induction chemotherapy prior to concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. However, the survival times were inferior to previously reported values for patients with stage III disease treated with concomitant chemoradiotherapy. The only other study addressing the role of induction chemotherapy was by Huang and colleagues who published a retrospective outcome analysis of 265 patients treated with definitive chemoradiotherapy for unresectable, locally advanced NSCLC, of whom 127 patients received induction chemotherapy (Huang et al, 2006). The induction chemotherapy group had an improved median OS of 1.9 years vs. 1.4 years for the group that did not receive induction chemotherapy. Five year survival rate significantly favored the induction chemotherapy group (25% vs. 12%; p<0.001). A subgroup analysis revealed that the survival benefit was isolated to those with adenocarcinoma or large cell carcinoma, but not squamous cell carcinoma. Thus, there may be a role for induction chemotherapy prior to chemoradiotherapy, but this is as yet undefined. Table 3. Outcomes of "equential vs. concurrent chemoradiotherapy. Study West Japan Lung Cancer Group RTOG 9410 Randomized patients Chemoradiotherapy treatment Concurrent Median survival (mos) Survival rate (%) (5-year) Sequential 13 9 (5-year) Concurrent (4-year) Sequential (4-year) P value Reference Furuse et al, 1999 Curran et al, 2003 Table 4. Grade 3 or greater acute toxicities comparing sequential chemoradiotherapy with concurrent chemoradiotherapy in RTOG 9410 (Curran et al, 2003). Toxicity (grade) Sequential chemoradiotherapy (%) Concurrent chemoradiotherapy (%) Esophagitis (3-4) Pneumonitis (3-5) Neutropenia (4-5) Thrombocytopenia (4-5) Any Grade

8 Sullivan et al: Diagnosis and multimodality management of stage III non-small cell lung cancer 5. Consolidation or maintenance chemotherapy following chemoradiotherapy Consolidation chemotherapy was incorporated in a treatment regimen for patients with unresectable stage IIIA/B disease by the SWOG, but recent studies do not support a survival benefit. Two phase II nonrandomized SWOG studies suggested that treating patients with three cycles of docetaxel consolidation therapy, following completion of definitive treatment with cisplatin and etoposide with concurrent thoracic RT, might improve survival (Albain et al, 2002; Gandara et al, 2003). Despite a lack of randomized studies, consolidation docetaxel has been used by 50% of surveyed oncologists (Green, 2007). Preliminary results from a study by Carter and colleagues, found a worse survival with the use of carboplatin, paclitaxel, and radiotherapy followed by consolidative weekly taxol vs. no consolidation therapy, primarily due to toxicity associated with consolidative therapy (Carter et al, 2006). Recently, the Hoosier Oncology Group randomized 203 patients who did not progress on cisplatin-etoposide and radiotherapy to 3 cycles of consolidation docetaxel vs. no consolidation. There was no difference between arms in survival (3 year survival 28%), and docetaxel consolidation was associated with increased toxicity (Bedano et al, 2007; Hanna et al, 2007). Kelly and colleagues evaluated 243 patients in 2007 with Stage III NSCLC treated with chemoradiotherapy with cisplatin and etoposide followed by docetaxel consolidation therapy, who were then randomized to receive Gefitinib maintenance therapy or placebo. Gefitinib maintenance therapy was associated with an inferior survival compared with placebo. C. Adjuvant therapy in resected patients Patients who are thought to have stage I or II disease preoperatively, who undergo surgical resection, may be discovered to have stage III disease in the final pathology specimen when mediastinal lymph node involvement is discovered. In one study, 13% of patients with clinical stage IA disease, who had a pre-operative high resolution CT scan without enlargement of mediastinal lymph nodes, were reclassified as stage IIIA disease after resection (Yoshino et al, 2006). Patients with stage III NSCLC that have been completely resected are at high risk of local recurrence and the development of distant metastatic disease. Improved survival with adjuvant chemotherapy with platinum-based drug regimens was confirmed in a meta-analysis that was presented at the American Society of Clinical Oncology (ASCO) annual meeting in June 2006 (Pignon et al, 2006) This meta-analysis pooled data from 5 large clinical trials, all of which used platinumbased chemotherapy and included 4584 patients. Three of the included trials allowed the use of thoracic RT at the discretion of the treating physician. Adjuvant chemotherapy was associated with an absolute increase in survival of 4.2 percent (hazard ratio [HR] 0.89, 95% CI ) at a median follow-up of 5.1 years. The data did not sort out the best agent to combine with cisplatin, and differing doses of cisplatin were used, depending on the trial. The International Adjuvant Lung Cancer Trial (IALT) examined cisplatin-based adjuvant chemotherapy versus observation in 1867 patients of whom 39% had stage III disease (Arriagada et al, 2004). With a median duration of follow-up of 56 months, the chemotherapy group had a significantly improved disease free survival (DFS) of 39.4% vs. 34.3% and OS of 44.5% vs. 40.4% compared with the observation group. The Adjuvant Navelbine International Trialist Association (ANITA) looked at adjuvant chemotherapy with cisplatin and vinorelbine versus observation in 799 patients with stage IB, II, or IIIA NSCLC, of whom 39% had stage IIIA disease (Douillard et al, 2006). RT was optional and was administered to 24% of patients in the chemotherapy group and 33% in the observation group. The median survival was significantly increased with chemotherapy, at a median follow-up of 76 months (66 vs. 44 months with observation). The absolute OS benefit with adjuvant chemotherapy was 8.6 percent at five years and 8.4 percent at seven years. The survival benefit was limited to patients with pathologic stage II or IIIA disease. Pathologic N2 disease was present in 27% of patients. Five year survival for the N2 subset was 40% (95% CI 30-49%) with chemotherapy vs. 19% (95% CI 11-27%) without chemotherapy. Of patients with N2 disease randomized to chemotherapy and who also received RT (n=73) 5 year survival was 47% as compared to 34% in those patients who did not receive RT (n=152). Of patients with N2 disease randomized to observation who received RT (n=128), 5 year survival was 21% as compared to 17% in those patients who did not receive any adjuvant therapy. Adjuvant chemoradiotherapy has not been shown to be beneficial over surgery alone in a randomized study of patients with completely resected stage II and stage IIIA NSCLC, suggesting a possible detriment from the RT component (Keller et al, 2000). However, if numerous mediastinal lymph nodes are involved, patients may benefit from adjuvant RT to the mediastinum. In a population-based cohort study, Lally and colleagues found in a subset analysis that post-operative RT was associated with a significant improved survival for patients with N2 disease (Lally et al, 2006). For patients with N0 or N1 disease, post-operative RT was associated with a significant decrease in survival. An American intergroup trial and an EORTC trial are presently underway to reevaluate the role of radiotherapy for patients with N2 disease using conformal techniques. The NCCN recommends adjuvant chemotherapy, for patients with stage IIIA disease after resection, with a cisplatin-based doublet but there is disagreement among panel members regarding the role of RT (NCCN Clinical Practice Guidelines in Oncology, 2008). A recent Cancer Care Ontario (CCO) and ASCO guideline recommends adjuvant cisplatin-based chemotherapy for patients with stage IIIA disease (Pisters et al, 2007). Due to the lack of prospective, randomized clinical trial data evaluating its efficacy, adjuvant RT was not recommended for patients with stage IIIA disease (Pisters et al, 2007). D. Special situations/considerations 1. Superior sulcus tumors Patients with superior sulcus (Pancoast) tumors with hilar lymph node involvement (T3, N1) are uncommon. 88

9 Cancer Therapy Vol 6, page 89 Improved outcomes with chemoradiotherapy in the treatment of non-pancoast, locally advanced, stage III NSCLC has led to its use in patients with superior sulcus tumors. Comparison to historical controls indicate that these patients should be treated with concurrent chemoradiotherapy, followed by surgical resection if there has not been progression of disease, and this is the approach recommended by the NCCN (NCCN Clinical Practice Guidelines in Oncology, 2008). A cooperative intergroup study evaluated concurrent chemotherapy (2 cycles of cisplatin and etoposide) with thoracic RT (45Gy in 25 fractions) followed by resection 3-5 weeks later (in those without progression of disease) and two additional cycles of postoperative chemotherapy in 111 patients with pathologically proven T3-4, N0-1 NSCLC presenting in the superior sulcus (Rusch et al, 2001, 2007). The percent of patients with N1 disease was not provided in the report, but 28% of patients had T4 tumors. Mature results of the study revealed a five year survival of 44% for all patients with no difference between T3 and T4 tumors. Japan Clinical Oncology Group Trial 9806 was a phase II study examining the efficacy and safety of preoperative chemoradiotherapy with two cycles of cisplatin, mitomycin, vindesine and 45Gy RT to the primary tumor and ipsilateral supraclavicular nodes in 76 patients with superior sulcus NSCLC (Kunitoh et al, 2008). Seventy four percent of the patients had T3 tumors and 26% had T4 disease. All of the T4 cases involved the spine. Induction therapy was completed in 95% of the patients and 76% underwent surgical resection. Complete resection was accomplished in 68% of the patients and 12 patients had a pathologic complete response. DFS and OS at 5 years was 45% and 56% respectively. 2. Satellite nodules Patients with T4N0-1 lesions, based upon the presence of satellite nodules within the same lobe as the primary tumor, may be candidates for surgical resection as the primary method of treatment. To illustrate this, Port and colleagues conducted a retrospective review of 53 patients with resected lung cancer containing intralobar satellite lesions and reported a 5-year OS rate of 47% for all patients in the study and an OS of 58% for those with N0 disease (Port et al, 2007). Treatment modalities other than surgery were not reported in this study. Osaki and colleagues conducted a retrospective review of 76 patients with surgically resected T4 NSCLC lesions, 36 of whom had satellite nodules. A 5-year OS rate of 26.7% was reported for the 36 patients, fifteen of whom received adjuvant chemotherapy and/or RT (Osaki et al, 2003). For resectable T4, N0-1 tumors due to satellite lesions, the NCCN recommends surgical resection followed by adjuvant chemotherapy (NCCN Clinical Practice Guidelines in Oncology, 2008). 3. Mediastinal invasion Patients with T4 tumors due to invasion of the mediastinum are generally unresectable and the standard treatment is chemoradiotherapy. Anecdotal experience suggests that neoadjuvant treatment with chemotherapy or chemoradiotherapy may be beneficial, enabling resection of tumors that respond to the neoadjuvant treatment (Albain et al, 1995). The NCCN is in agreement with this approach (NCCN Clinical Practice Guidelines in Oncology, 2008). The Spanish Lung Cancer Group Trial 9901 (described above) included 34 patients with tumor infiltration of the great vessels, 2 patients with tracheal infiltration, 6 patients with invasion of the carina, 2 patients with infiltration of the esophagus, 4 patients with invasion of the heart and 22 patients with mediastinal invasion (Garrido et al, 2007). The patients received induction chemotherapy followed by surgery in responding patients. The survival was similar to that of stage IIIA (N2) patients (median survival of 15.6 and 16.8 months for patients with stage IIIA and IIIB disease, respectively). 4. Targeted therapy The tyrosine kinase signaling pathway, including the epidermal growth factor receptor (EGFR) is known to be altered in NSCLC. EGFR is overexpressed in a variety of tumors including NSCLC. Erlotinib, a small molecule EGFR inhibitor, is approved for use as second-line treatment of metastatic NSCLC (Shepherd et al, 2005). Additionally, the anti-vascular endothelial growth factor inhibitor bevacizumab has improved survival in first-line treatment of metastatic NSCLC when combined with carboplatin and paclitaxel (Sandler et al, 2006). The optimal use of targeted therapies in the neoadjuvant, adjuvant or definitive treatment of stage III NSCLC remains to be defined. 5. Immunotherapy A goal of cancer research has been to incite an immune response against cancer cells. Tumor antigens can stimulate an immune response and the use of tumor vaccines may have a role in resectable and unresectable NSCLC in conjuction with conventional therapies. Tumor vaccines have been used to target known tumor-specific antigens and, in an autologous fashion, to target unique antigens derived from a patient s own tumor. Dendritic cells are antigen-presenting cells under investigation in tumor vaccine development and have been shown to have therapeutic potential (Hirschowitz et al, 2004, Ishikawa et al, 2005). Encouraging results in NSCLC patients immunized with an autologous tumor cell vaccine expressing granulocyte macrophage colony stimulating factor (GM-CSF) support the rationale for further investigation (Nemunaitis et al, 2004). Muc 1 is a cell surface glycoprotein overexpressed in NSCLC and has been administered as a liposomal vaccine to stimulate an immune response. A phase II trial in patients with advanced stage NSCLC showed a trend toward improved survival with use of the vaccine compared with best supportive care (Butts et al, 2005). A phase III trial is underway. Further investigation of immunotherapy in NSCLC is warranted. 6. Prophylactic cranial irradiation (PCI) Patients with stage III NSCLC are at high risk of developing CNS metastases, suggesting a role for PCI. A SWOG retrospective study found that 26% of patients 89

10 Sullivan et al: Diagnosis and multimodality management of stage III non-small cell lung cancer with stage III NSCLC subsequently develop brain metastases and were more common in patients under the age of 60 and with non-squamous histologies(gaspar et al, 2005). A German randomized trial with 112 patients examined the role of PCI following a trimodality treatment protocol of chemotherapy, chemoradiotherapy and surgery in patients with operable stage IIIA NSCLC (Pöttgen et al, 2007). PCI significantly reduced the probability of brain metastases as the first site of failure (7.8% vs. 34.7% at 5 years, p=0.02) and reduced the overall brain relapse rate (9.1% vs. 27.2% at 5 years, p=0.04). There was no difference in 5-year OS (18%). Neurocognitive late effects in 11 long-term survivors were not significantly different between those patients treated with or without PCI. The RTOG is presently conducting a study of patients with stage III non-small cell carcinoma who do not have progressive disease to evaluate the potential benefit of PCI. Patients will be randomized to 30Gy in 15 fractions vs. observation after definitive local therapy. The primary endpoint is survival and secondary endpoints are the rate of CNS metastasis, quality of life, and neurocognitive effects. IV. Conclusions Patients with stage III NSCLC encompass a heterogeneous group whose optimal management approach is dependent on multiple factors and remains to be defined for some patients. A combined modality approach with concurrent chemoradiotherapy with a platinum-based regimen has become the preferred treatment for the majority of patients with stage III disease detected clinically. The role of surgery in patients with pre-operatively detected but non-bulky mediastinal lymph node involvement and T1-3 primary tumors who respond to chemotherapy or chemoradiotherapy remains unclear, but seems reasonable in those patients with down-staged nodal disease after induction therapy who do not require pneumonectomy. Adjuvant platinum-based chemotherapy should be offered to those patients found to have stage III disease at the time of surgery. There is vast room for improving outcomes for patients with this disease. A multidisciplinary approach to managing this diverse group of patients is recommended. References Albain KS, Crowley JJ, Turrisi AT 3rd, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB. 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