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doi:10.1378/chest.07-1380
(Chest. 2007; 132:266S-276)
© 2007 American College of Chest Physicians
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Treatment of Non-small Cell Lung Cancer, Stage IIIB*

ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

James R. Jett, MD, FCCP; Steven E. Schild, MD; Robert L. Keith, MD, FCCP and Kenneth A. Kesler, MD, FCCP

* From the Division of Pulmonary Medicine and Medical Oncology (Dr. Jett), Mayo Clinic, Rochester, MN; the Department of Radiation Oncology (Dr. Schild), Mayo Clinic, Scottsdale, AZ; the Division of Pulmonary Sciences and Critical Care Medicine (Dr. Keith), Denver VA Medical Center, University of Colorado Health Sciences Center, Denver, CO; and the Division of Thoracic Surgery (Dr. Kesler), Indiana University, School of Medicine, Indianapolis, IN.

Correspondence to: James R. Jett, MD, FCCP, Division of Pulmonary Medicine and Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: JETT.JAMES{at}mayo.edu


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Objective: To develop evidence-based guidelines on best available treatment options for patients with stage IIIB non-small cell lung cancer (NSCLC).

Methods: A review was conducted of published English-language (abstract or full text) phase II or phase III trials and guidelines from other organizations that address management of the various categories of stage IIIB disease. The literature search was provided by the Duke University Center for Clinical Health Policy Research and supplemented by any additional studies known by the authors.

Results: Surgery may be indicated for carefully selected patients with T4N0-1M0. Patients with N3 nodal involvement are not considered to be surgical candidates. For individuals with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy (RT) alone. Concurrent chemoradiotherapy seems to be associated with improved survival compared with sequential chemoradiotherapy. Multiple daily fractions of RT when combined with chemotherapy have not been shown to result in improved survival compared with standard once-daily RT combined with chemotherapy. The optimal chemotherapy agents and the number of cycles of treatment to combine with RT are uncertain.

Conclusion: Prospective trials are needed to answer important questions, such as the role of induction therapy in patients with potentially resectable stage IIIB disease. Future trials are needed to answer the questions of optimal chemotherapy agents and radiation fractionation schedule. The role of targeted novel agents in combination with chemoradiotherapy is just starting to be investigated.

Key Words: chemoradiotherapy • hyperfractionated radiotherapy • radiotherapy • treatment stage IIIB


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StageIIIB non-small cell lung cancer (NSCLC) includes patients with T4 tumors; any N; M0; and any T, N3, M0.1 It is estimated that 10 to 15% of all patients are at stage IIIB at the time of diagnosis of their disease.1 On the basis of the Surveillance, Epidemiology, and End Results registry 2004, Wisnivesky et al2 evaluated >80,000 cases of NSCLC with adequate documentation of tumor size (53% of total Surveillance, Epidemiology, and End Results registry) and reported that 17.6% were stage IIIB. The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3 to 7%.1 Data on pathologically staged IIIB disease was not available from the Mountain International Classification but will be included in the revised international staging system that is planned for 2009.

The optimal treatment for stage IIIB NSCLC depends on several variables, including the extent of disease, age, comorbid risk factors, patient performance status (PS), and weight loss. Radiotherapy (RT) alone has been used in the past but should be limited to patients with poor PS. Chemotherapy alone is similarly not a good treatment option, except for patients with malignant pleural effusions (discussed in the "Treatment of Non-small Cell Lung Cancer, Stage IV" chapter). Palliative chemotherapy is not addressed in this article. Surgery can be offered to highly selected patients, either as a single modality or after induction (neoadjuvant) chemotherapy with or without RT. Concurrent chemoradiotherapy is recommended for most cases.


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This section of the evidence-based guidelines is based on an extensive review of the medical literature from 2002 through mid-2006. A literature search was provided by the Duke University Center for Clinical Health Policy Research and supplemented by additional studies known by the authors. These reports included selected case series and pooled data analysis for rare clinical situations, such as superior vena cava (SVC) resection for T4 tumors. Data from four additional guidelines published since 2002 was reviewed along with 10 phase III trials and numerous phase II treatment trials addressing the more common treatment questions related to stage IIIB disease. Recommendations were developed by the writing committee, graded by a standardized method (see "Methodology for Lung Cancer Evidence Review and Guideline Development" chapter), and reviewed by all members of the lung cancer panel before approval by the Thoracic Oncology NetWork, Health and Science Policy Committee, and the Board of Regents of the American College of Chest Physicians.


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Limited Role of Surgery
Surgery may be indicated for meticulously culled patients with stage IIIB disease3 (see "Special Treatment Issues in Lung Cancer" chapter). Patients who have T4N0-1 solely on the basis of a satellite tumor nodule(s) within the primary lobe have been reported to have 5-year survival rate of approximately 20%. These reports456 are retrospective case series and pooled data analysis. Carinal resections with lobectomy or pneumonectomy have been performed for T4N0-1 disease.78910 Carinal resections carry an appreciable operative mortality of 10 to 15% in experienced centers.78 Sleeve pneumonectomy has been estimated to have an operative mortality two to four times that of standard pneumonectomy.9 The 5-year survival in these carefully selected retrospective series is approximately 20%. Similarly, surgical resection of the SVC for direct tumor invasion has been performed selectively.1112 A review11 of 109 SVC resections from four international centers included 78 cases of resection for tumor involvement of the SVC and 31 cases for mediastinal lymph nodal involvement of the SVC. Fifty percent of the cases required a pneumonectomy. The operative mortality rate was 12%, and the 5-year survival rate was 21%. Both pneumonectomy and complete resection of the SVC with a prosthetic replacement were associated with a significant increased risk for death.

Trials of neoadjuvant chemotherapy or chemoradiotherapy followed by surgical resection have generally excluded patients with stage IIIB disease. Reports131415 of carefully chosen patients with stage IIIB disease have shown a similar survival to patients with stage IIIA disease when treated with induction therapy followed by resection. The overall 5-year survival rate is ≤20%. However, the subset of patients who have stage IIIB disease and demonstrate a complete pathologic response after induction therapy with no residual viable neoplasm identified in the surgical specimen may experience better survival rates. In patients who have stage IIIB NSCLC and are believed to be surgical candidates but are anticipated to require pneumonectomy, surgery with consideration of adjuvant chemotherapy without RT may be a preferable treatment option, because induction chemoradiation therapy followed by pneumonectomy has been shown to be associated with significant mortality risk.16 For patients with stage IIIB disease and T4 tumors, the presence of N2 disease is considered to be a strong contraindication to surgery, which is consistent with the British Thoracic Society and National Comprehensive Cancer Network guidelines.317 To date, no phase III data demonstrate that neoadjuvant treatment followed by surgery in patients with IIIB disease results in prolonged survival compared with treatment with chemoradiation therapy without surgery. Given the apparent low benefit/risk ratio, any patient who has clinical stage IIIB and is believed potentially to be a surgical candidate would best be evaluated by several disciplines, including a pulmonologist, medical and radiation oncologists, and thoracic surgeon, before treatment.


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1. In selected patients with clinical T4N0-1 NSCLC as a result of satellite tumor nodule(s) in the same lobe, carinal involvement, or SVC invasion, it is recommended that evaluation be performed by a multidisciplinary team that includes a thoracic surgeon with lung cancer expertise to determine whether the tumor is operable. Surgery is not recommended when there is N2 involvement. Grade of recommendation, 1C

2. For patients with stage IIIB NSCLC as a result of N3 disease, treatment with neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery is not recommended. Grade of recommendation, 1C

RT Alone vs Combination Chemoradiotherapy
The vast majority of patients with IIIB disease do not benefit from surgery and are best treated with chemoradiotherapy or RT alone, depending on sites of tumor involvement, extent of disease, and PS. Since the American College of Chest Physicians guidelines in 2003, four additional guidelines have been published by the American Society of Clinical Oncology, Cochrane group, National Comprehensive Cancer Network, and Cancer Care Ontario.17181920 The data for these guidelines were derived from randomized, prospective trials that evaluated patients with both unresectable IIIA and IIIB disease. Results of patients with IIIB disease alone are not independently available. Data in the Cancer Care Ontario guidelines included six metaanalyses and 17 randomized trials of chemotherapy vs RT.20 The largest metaanalysis was performed by the NonSmall Cell Lung Cancer Collaborative Group as referenced in the last American College of Chest Physicians guidelines21; of 22 randomized trials evaluated, only 11 of these trials were with cisplatin-based chemotherapy. The trials with non–cisplatin-based chemotherapy did not demonstrate any survival benefit. The results showed a significant benefit with cisplatin-based chemoradiotherapy. There was a 13% reduction in the risk for death (hazard ratio, 0.87) and an absolute benefit of 4% at 2 years and 2% at 5 years (p = 0.005). Results of all four practice guidelines favored cisplatin-based chemoradiotherapy vs RT alone for patients with good PS (0 or 1) and minimal weight loss (≤5%).


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3. For patients with stage IIIB disease without malignant pleural effusions, PS of 0 or 1, and minimal weight loss (≤5%), platinum-based combination chemoradiotherapy is recommended. Grade of recommendation, 1A

4. In patients with stage IIIB NSCLC and PS of 2 or those with substantial weight loss (>10%), chemoradiotherapy is recommended only after careful consideration. Grade of recommendation, 1C

Concurrent vs Sequential Therapy
Phase III trials have been performed to compare sequential and concurrent radiation and chemotherapy. The West Japan Lung Cancer Group conducted a randomized phase III trial of concurrent vs sequential thoracic RT and cisplatin-based chemotherapy with >150 patients in each arm.22 Seventy-two percent had stage IIIB disease. Radiation was begun on day 2 (2 Gy per fraction for 14 days) followed by a 10-day rest and then repeated for a total dose of 56 Gy. In the sequential study arm, the same chemotherapy was administered but RT was initiated after chemotherapy was completed and consisted of 56 Gy (2 Gy per fraction for 14 days) without a break. The median survival time (MST) was superior for patients who were in the concurrent therapy study arm (16.5 months vs 13.3 months), and the 5-year survival difference was 15.8% vs 8.9% (p = 0.039; Table 1 ).


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  		Table 1.. Phase III Trials Comparing Concurrent With Sequential Chemoradiotherapy for Stage III NSCLC: 1995 to Present

 
The Radiation Therapy Oncology Group (RTOG) conducted a phase III trial (RTOG-9410) that compared concurrent with sequential chemoradiotherapy.23 The chemotherapy was vinblastine and cisplatin. Radiation was begun on day 1 with chemotherapy or day 50 after chemotherapy. The total dose was 63 Gy. A third arm in the trial evaluated concurrent bid RT (69.6 Gy in 1.2-Gy bid fractions) with cisplatin and oral etoposide.23 The median and 4-year survival rates were 17 months and 21%, respectively, on the concurrent therapy arm with once-daily radiation and 14.6 months and 12%, respectively, on the sequential treatment study arm (p = 0.046). The twice-daily radiation arm had an intermediate survival rates of 15.2 months and 17%, respectively.

A French phase III trial of concurrent vs sequential chemoradiotherapy randomly assigned 205 patients. RT administered was 66 Gy in 33 fractions.26 Chemotherapy consisted of vinorelbine and cisplatin for three cycles followed by RT, or concurrent cisplatin and etoposide for two cycles with RT followed by cisplatin and vinorelbine for two additional cycles of consolidative therapy. MSTs were 16.3 months vs 14.5 months in favor of concurrent therapy (p = 0.24). The 2-, 3-, and 4-year survival rates were better in the concurrent study arm (39%, 25%, and 21%, respectively) than in the sequential study arm (26%, 19%, and 14%, respectively).

A trial27 from the Czech Republic randomly assigned 102 patients (85% with stage IIIB disease) to concurrent (started day 4 of cycle 2) or sequential RT after four cycles of vinorelbine and cisplatin. The concurrent study arm had the superior survival with MST and 3-year survival rates of 16.6 months and 18.6% vs 12.9 months and 9.5%, respectively. The hazard ratio was 0.61 in favor of concurrent therapy.27

All of these trials have shown that concurrent chemoradiotherapy is associated with increased toxicity, primarily esophagitis, and some trials showed increased neutropenia and nausea/vomiting (Table 2 ). Concurrent therapy did not increase the number of treatment-related deaths The most common chemotherapeutic agents used concurrently with RT have been vinorelbine, vinblastine, and etoposide in conjunction with cisplatin or weekly paclitaxel and carboplatin.282930 No randomized phase III trials of concurrent chemoradiotherapy have shown the superiority of one chemotherapy regimen over another. The consensus opinion reported in the Cancer Care Ontario Guidelines 200520 was that there are insufficient data to determine the most effective chemotherapy.


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  		Table 2.. Summary of Survival and Toxicity From Trials Comparing Concurrent With Sequential Chemoradiotherapy*

 
One phase II trial and one phase III trial2829 have evaluated induction chemotherapy followed by concurrent chemoradiotherapy vs initial treatment with concurrent therapy followed by consolidative treatment. In the randomized phase II trial,2729 concurrent weekly paclitaxel, carboplatin, and thoracic RT followed by consolidative therapy seemed to have the best outcome vs sequential chemoradiotherapy or induction chemotherapy followed by identical concurrent chemoradiotherapy (MST, 16.3 months vs 13 months or 12.7 months). However, this was a phase II trial, and it was not designed to compare the three study arms directly. A phase III trial was conducted by the Cancer and Acute Leukemia Group B,28 who compared immediate treatment with weekly paclitaxel/carboplatin and thoracic RT (study arm 1) with two cycles of induction paclitaxel and carboplatin followed by identical concurrent chemoradiotherapy (study arm 2). No consolidative treatment was administered in either study arm.28 MSTs (11.4 months and 13.7 months [study arm 2]) and 3-year survival rates (18% and 24% [study arm 2]) were similar and not statistically different (p = 0.14). The authors28 concluded that induction chemotherapy followed by concurrent chemoradiotherapy was not superior to initial treatment with concurrent therapy. Because of the poor overall results, they questioned whether the low-dose weekly chemoradiotherapy approach might be inferior to the approach with full-dose chemotherapy and thoracic RT.

Southwestern Oncology Group investigators30 have reported some of the best results from a single-arm phase II trial for patients with stage IIIB disease. This trial included concurrent full-dose etoposide and cisplatin and thoracic RT followed by consolidative docetaxel chemotherapy.30 MST was 26 months, and the 3-year survival rate was 37%. These results are awaiting confirmation in a phase III trial. All patients will receive identical initial treatment with concurrent chemoradiotherapy and are randomly assigned to consolidative docetaxel or no consolidative treatment. It is uncertain how many cycles of chemotherapy are optimal in treatment of patients with stage III disease. The American Society of Clinical Oncology guidelines recommend two to four cycles of platinum-based chemotherapy. Two cycles should be administered concurrently with thoracic RT.18


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5. For patients with stage IIIB NSCLC and PS 0 or 1 and minimal weight loss (≤5%), concurrent chemoradiotherapy is recommended. Grade of recommendation, 1A

6. The most efficacious chemotherapy drugs to be combined with thoracic RT and the number of cycles of chemotherapy needed to yield the best results are uncertain. No one combination chemotherapy regimen can be recommended. Grade of recommendation, 2C

Radiation Dose Fractionation Studies
Multiple trials have explored the use of altered-dose fractionation schedules as a means of improving the therapeutic index. Two general approaches have been evaluated. Pure hyperfractionated RT uses two or three small doses of RT per day administered over the standard treatment duration. Because smaller radiation fractions result in less damage to normal tissues as compared with rapidly replicating tumor cells, this permits an increase in the total radiation dose administered to the tumor without worsening normal tissue toxicity. Pure accelerated fractionation RT administers the same total dose using standard fraction sizes that are administered multiple times per day. This results in a decrease in the overall treatment time and provides greater tumor kill because there is less time between treatments for repopulation by rapidly growing cells. Most clinical trials have combined accelerated fractionation and hyperfractionated RT in a hybrid approach, termed accelerated hyperfractionated RT (Table 3 ).


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  		Table 3.. Phase III Trials Evaluating Multiple Daily Fractions of RT Compared to Once-Daily Fractions of RT for Stage III NSCLC (1995-present)*

 
Randomized prospective studies have failed to demonstrate an advantage for twice-daily RT compared with once-daily RT for stage III NSCLC. The RTOG performed a randomized, prospective study2334 (RTOG 9410) to compare chemotherapy plus either twice-daily RT or once-daily RT for locally advanced NSCLC. Patients were randomly assigned to three study arms and received sequential therapy with cisplatin plus vinblastine followed by 63 Gy in 34 daily fractions; concurrent therapy with cisplatin, vinblastine, and 63 Gy in 34 daily fractions; or concurrent twice-daily RT (69.6 Gy in 1.2-Gy fractions bid) with cisplatin and oral etoposide. The median and 4-year survival rates were 17 months and 21% in the concurrent once-daily RT study arm, 14.6 months and 12% in the sequential once-daily RT study arm, and 15.2 months and 17% in the concurrent twice-daily RT study arm. The difference in survival between the concurrent once-daily RT study arm and the sequential once-daily RT study arm was significant (p = 0.046). In addition to the RTOG 9410 trial, a phase III study35 was performed by the North Central Cancer Treatment Group (94-24-52) to compare concurrent etoposide plus cisplatin with either standard once-daily RT (60 Gy in 30 daily fractions) or etoposide and cisplatin plus split-course twice-daily RT (60 Gy in 40 fractions bid with a 2-week break in the middle). MST and 5-year survival rates for the once-daily RT study arm were 14 months and 13%, respectively, vs 15 months and 20%, respectively, for the twice-daily RT study arm (p = 0.4). There was no advantage to twice daily RT with regard to survival, disease control, or toxicity in either trial.

RT three times daily has shown promise for NSCLC. Saunders et al33 performed a randomized study that compared once-daily RT (60 Gy in 30 fractions over 6 weeks) with continuous hyperfractionated accelerated RT (CHART) 54 Gy in 36 fractions tid (6 h apart over 12 total days). Sixty-one percent of patients had stage IIIA or IIIB disease. No chemotherapy was administered. Patients who received CHART had a 2-year survival rates of 29%, vs 20% in those who received once-daily (p = 0.008). These findings demonstrate the critical importance of the overall treatment time on RT outcome. CHART was delivered in only 12 days, whereas the twice -daily RT programs used in North Central Cancer Treatment Group 94-24-52 and RTOG 9410 were approximately 6 weeks long. Accelerated repopulation of tumor cells during RT occurred to a lesser degree during CHART, yielding more favorable results. However, the CHART trial lacked chemotherapy, which seems to be a critically important addition to RT (Table 3).

The Eastern Cooperative Oncology Group (ECOG) initiated a phase III trial (E-2597) of chemotherapy (two cycles of paclitaxel and carboplatin) followed by either once-daily RT (64 Gy in 32 fractions for 6.5 weeks) or three-times-daily RT (57.6 Gy in 36 fractions for 12 weekdays) for stage III NSCLC.36 Unfortunately, accrual was slow and the study was closed before completion. MSTs were 14.9 months with once-daily RT vs 20.3 months with three-times-daily RT (p = not significant).

Very few patients have been treated with concurrent chemotherapy and three-times-daily RT. Oral et al37 reported a 20-patient trial that included concurrent CHART and paclitaxel. Unfortunately, this resulted in excessive toxicity, with 50% of patients having grade 3 or greater pneumonitis. Mayo Clinic investigators31 performed a trial with 20 patients who were treated with escalating doses of daily cisplatin administered concurrently with the same regimen of three-times-daily RT used in the ECOG trial. The maximum tolerated dose of daily cisplatin was 7.5 mg/d. The median survival was 22 months, and 5-year survival was 25%.31

For patients with stage IIIB NSCLC, there are convincing data that RT three times daily (CHART) alone is better than standard once-daily RT alone. However, there are problems that preclude this type of RT from being recommended for use. First, CHART is logistically difficult and has not been embraced by most radiation oncology facilities worldwide. Second, there is definitive proof that systemic chemotherapy improves survival when added to RT, especially when the two therapies are administered concurrently. Integrating chemotherapy with RT three times daily has posed difficult challenges. There has been some use of sequential therapy and a very small experience with concurrent therapy. No phase III trials have proved that chemotherapy plus multiple daily fraction RT yields significantly better survival than chemotherapy plus once-daily RT (Table 3). Although ECOG 2597 was provocative, it was never completed, leaving unanswered the question as to whether RT three times daily would be better than once-daily RT when used as part of a combined modality program.


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7. For patients with stage IIIB NSCLC, once-daily thoracic RT plus chemotherapy is recommended. Grade of recommendation, 1B

Palliation of Lung Cancer With RT
A patient can be treated with curative intent when the disease can be contained within a reasonable RT field. In addition, the patient should be physically fit enough to withstand the effects of therapy. Usually, patients are considered able to withstand potentially curative therapy when they have Zubrod PS of 0 to 2 and adequate pulmonary function (spirometry with FEV1 ≥1 L/s).

The most common symptoms that are considered for palliative thoracic RT include dyspnea, cough, hemoptysis, and pain. These symptoms occur as a result of tumor-related obstruction and irritation of the normal intrathoracic structures. In addition, RT is frequently used for the palliation of metastases to other normal structures, such as the brain, spine, or bones (palliation of sites outside the chest are covered elsewhere).

Many studies383940414243444546474849505152 have been performed to identify the optimal thoracic RT regimen for the palliation of NSCLC. The perfect regimen would rid the patients of all symptoms permanently, cause no adverse effects, extend survival, and require little time. Clearly, these goals are not 100% attainable, but one should strive to maximize palliation and minimize adverse effects. Several phase III trials have compared various RT dose-fractionation regimens. Most of these trials detected no significant benefit for the study of RT regimens. Of the phase III trials performed, the trials that had positive findings are reviewed here. There is heterogeneity among the trials in intent and design, which makes them difficult to compare directly with one another.

Nestle et al47 and Macbeth et al50 performed a trial that included 509 patients with nonmetastatic inoperable NSCLC that was too extensive for radical RT. Patients received either 17 Gy in two fractions (F2) 1 week apart or 39 Gy in 13 fractions (F13) 5 d/wk. Survival was better in the F13 group; MST was 7 months in the F2 group, compared with 9 months in the F13 group (p = 0.03). The most common symptoms were cough, shortness of breath, fatigue, worrying, and chest pain. These were more rapidly palliated by the F2 regimen. Three patients (two F13, one F2) exhibited evidence of myelopathy. Nestle et al47 and Macbeth et al50 concluded that the F2 regimen had a more rapid palliative effect, but survival was longer in the F13 group.

Teo et al39 performed a trial that included 291 patients who had inoperable advanced NSCLC and were randomly assigned to 45 Gy in 18 fractions for 4.5 weeks administered in study arm 1 or 31.2 Gy in four fractions for 4 weeks administered in study arm 2. MST was 20 weeks and was similar in both study arms. Study arm 1 was superior to study arm 2 in achieving symptom palliation (71% vs 54%; p < 0.02). Both study arms were equally well tolerated. Toxicity was mild and included radiation esophagitis, pneumonitis, and pulmonary fibrosis.

Reinfuss et al44 included 240 patients with stage III, unresectable, asymptomatic NSCLC and were randomly assigned to one of the three treatment arms: conventional RT, hypofractionated RT, and a control group treated with delayed RT when symptoms required treatment. In the conventional irradiation treatment arm (79 patients), a dose of 50 Gy in 25 fractions in 5 weeks was delivered to the primary tumor and the mediastinum. In the hypofractionated irradiation treatment arm (81 patients), two courses of irradiation were separated by an interval of 4 weeks. Each of the two courses included 20 Gy in five fractions in 5 days to the same treatment volume as the conventional irradiation group. The delayed RT arm included 80 patients who received a single course of palliative hypofractionated irradiation (20 to 25 Gy in four to five fractions in 4 to 5 days) administered to the primary tumor. The 2-year actuarial survival rates for patients in the conventional irradiation, hypofractionated irradiation, and control group arms were 18%, 6%, and 0%, with MSTs of 12 months, 9 months, and 6 months, respectively. The differences between survival rates were statistically significant. The comparison of conventional and hypofractionated irradiation shows a survival advantage for the conventional schedule.

Bezjak et al48 randomly assigned 230 patients to either 10 Gy in one fraction or 20 Gy in five fractions. The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT (five fractions) group had greater improvement in symptoms related to lung cancer (p = 0.009), pain (p = 0.0008), ability to carry out normal activities (p = 0.037), and better global quality of life (p = 0.039). The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients who received five fractions had a greater improvement in scores with respect to pain (p = 0.04). No significant difference was found in treatment-related toxicity. Patients who received five fractions survived on average 2 months longer (p = 0.0305) than patients who received one fraction. They concluded that the fractionated regimen was preferable.

Erridge et al46 performed a phase III trial to determine whether palliation of chest symptoms from a 10-Gy single fraction was equivalent to that from 30 Gy in 10 fractions. They randomly assigned 149 patients and analyzed 74 patients in each treatment arm. The total symptom score improved in 49 patients (77%) with 10 Gy and in 57 patients (92%) with 30 Gy, a difference of 15%, which was not significantly different. However, complete resolution of all symptoms was achieved in 3 patients (5%) with 10 Gy and in 14 patients (23%) with 30 Gy (p < 0.001). Although this trial met the predetermined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnea with the fractionated regimen.

Kramer et al49 compared the efficacy of 2 x 8 Gy vs 10 x 3 Gy in 297 patients with inoperable stage IIIA/B (with an ECOG PS of 3 to 4 and/or substantial weight loss) and stage IV NSCLC. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms. Palliation in the 10 x 3-Gy treatment arm was more prolonged (until week 22) with fewer worsening symptoms than in the 2 x 8-Gy treatment arm. Survival in the 10 x 3-Gy treatment arm was significantly (p = 0.03) better than in the 2 x 8-Gy treatment arm, with 1-year survival rates of 19.6% vs 10.9%. They concluded that the 10 x 3-Gy RT schedule was preferred over the 2 x 8-Gy schedule for palliative treatment because it improved survival and resulted in a longer duration of the palliation.

Senkus-Konefka et al51 compared two palliative RT schedules for inoperable symptomatic NSCLC. One hundred patients were randomly assigned to 20 Gy in five fractions for 5 days (treatment arm A) or 16 Gy in two fractions for 1 and 8 days (treatment arm B). Treatment tolerance was good and did not differ between study arms. No significant differences between study arms were observed in the degree of relief of symptoms. Overall survival time differed significantly in favor of treatment arm B (median, 8.0 months vs 5.3 months; p = 0.016). Both irradiation schedules provided comparable, effective palliation of tumor-related symptoms. The improved overall survival and treatment convenience of a two-fraction schedule suggest its usefulness in the routine management of symptomatic inoperable NSCLC.

Radiation myelopathy (RM) is one of the most serious and feared complications of RT. Macbeth et al52 described the Medical Research Council Lung Cancer Working Party experience. Five cases of RM occurred among 1,048 patients who had inoperable NSCLC and were treated with palliative RT in three randomized trials. Seven RT regimens were used in these trials: 10 Gy in a single fraction on 1 day (114 patients); 17 Gy in two fractions over 8 days (524 patients); 27 Gy in six fractions over 11 days (47 patients); 30 Gy in six fractions over 11 days (36 patients); 30 Gy in 10 fractions over 12 days (88 patients); 36 Gy in 13 fractions over 16 days (86 patients); and 39 Gy in 13 fractions over 17 days (153 patients). Of the five instances of RM, three occurred in the 524 patients who were treated with 17 Gy in 2 fractions and two in the 153 patients who were treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17-Gy group, 2.5% for the 39-Gy group, and 0% for the remainder. This suggests that one might consider avoiding the regimens of 17 Gy in 2 fractions over 8 days and 39 Gy in 13 fractions over 12 days to avoid this potential devastating complication.

The general trend in studies with positive findings were that higher dose, more fractionated regimens resulted in better palliation and longer survival. This is not a particular surprise because palliation of tumor-related symptoms requires the death of enough tumor cells to relieve pressure and irritation of normal structures. As is true of all treatment, there seems to be dose dependence in achieving the desired outcome, symptomatic relief. The most commonly used palliative RT regimen is 30 Gy in 10 fractions, which would be a reasonable choice for a patient who requires palliative RT for thoracic symptoms. However, the use of common sense in customizing therapy to the needs of the patient is still the best approach. A patient with good PS could be treated with a longer fractionated regimen as opposed to a very ill-appearing patient who has poor PS and may be better served with a short regimen, such as 10 Gy in one fraction or 16 Gy in two fractions (days 1 and 8). Because of the Medical Research Council findings of RM in some patients, one might consider avoiding the regimens of F2 for 8 days and F13 for 12 days.

For patients who have stage IIIB disease and poor PS or disease that is too extensive to treat with curative intent and symptoms as a result of chest disease, palliative RT is recommended. The fractionation pattern should be chosen on the basis of the physician’s judgment and the patient’s needs. Patients who seem to be more vigorous should be treated with a longer RT program because this will likely palliate symptoms for a greater period and may increase survival. Representative RT regimens were already presented. Patients with very tenuous health and very short estimated survival should be treated with a short course of RT because it is likely that this will help the symptoms without using up a great amount of their limited lifespan.


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8. For patients with stage IIIB disease, either poor PS or disease that is too extensive to treat with curative intent, and symptoms as a result of chest disease, palliative RT is recommended. The fractionation pattern should be chosen on the basis of the physician’s judgment and the patient’s needs. Grade of recommendation, 1A


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 Summary of Recommendations
References
 
1. In selected patients with clinical T4N0-1 NSCLC as a result of satellite tumor nodule(s) in the same lobe, carinal involvement, or SVC invasion, it is recommended that evaluation be performed by a multidisciplinary team that includes a thoracic surgeon with lung cancer expertise to determine whether the tumor is operable. Surgery is not recommended when there is N2 involvement. Grade of recommendation, 1C

2. For patients with stage IIIB NSCLC as a result of N3 disease, treatment with neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery is not recommended. Grade of recommendation, 1C

3. For patients with stage IIIB disease without malignant pleural effusions, PS of 0 or 1, and minimal weight loss (≤5%), platinum-based combination chemoradiotherapy is recommended. Grade of recommendation, 1A

4. In patients with stage IIIB NSCLC and PS of 2 or those with substantial weight loss (>10%), chemoradiotherapy is recommended only after careful consideration. Grade of recommendation, 1C

5. For patients with stage IIIB NSCLC and PS of 0 or 1 and minimal weight loss (≤5%), concurrent chemoradiotherapy is recommended. Grade of recommendation, 1A

6. The most efficacious chemotherapy drugs to be combined with thoracic RT and the number of cycles of chemotherapy needed to yield the best results are uncertain. No one combination chemotherapy regimen can be recommended. Grade of recommendation, 2C

7. For patients with stage IIIB NSCLC, once-daily thoracic RT plus chemotherapy is recommended. Grade of recommendation, 1B

8. For patients with stage IIIB disease, either poor PS or disease that is too extensive to treat with curative intent, and symptoms as a result of chest disease, palliative RT is recommended. The fractionation pattern should be chosen on the basis of the physician’s judgment and the patient’s needs. Grade of recommendation, 1A


   Footnotes
 
Abbreviations: CHART = continuous hyperfractionated radiotherapy; ECOG = Eastern Cooperative Oncology Group; F2 = 17 Gy in two fractions; F13 = 39 Gy in 13 fractions; MST = median survival time; NSCLC = non-small cell lung cancer; PS = performance score; RM = radiation myelopathy; RT = radiotherapy; RTOG = Radiation Therapy Oncology Group; SVC = superior vena cava

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 30, 2007. Accepted for publication June 5, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Recommendations
 Recommendations
 Recommendations
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 Summary of Recommendations
 References
 

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