1. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111(6):1710-1717.
15 5,319 Present revisions in stage grouping of the TNM subsets (T = primary tumor, N = regional lymph nodes, M = distant metastasis) in the International System for Staging Lung Cancer. Study analyzed database representing all clinical, surgical-pathologic, and follow-up information for patients treated for primary lung cancer. Revisions addressed two problems; the heterogeneity of end results existing for the TNM categories within stage groups, and a need for greater specificity in stage classification.
The TNM subsets in stage IIIB — T4 any N M0, any T N3M0, and in stage IV — any T any N M1, remain the same. Analysis of database confirmed the validity of the TNM and stage grouping classification schema.
2
2. Greene FL, Page DL, Fleming ID, et al, eds, for the American Joint Committee on Cancer. AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2002.
15 N/A Cancer staging manual. N/A N/A
3. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2(8):706-714.
15 67,725 cases Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumors.
Suggestions include additional cutoffs for tumor size, with tumors >7 cm moving from T2 to T3; reassigning the category given to additional pulmonary nodules in some locations; and reclassifying pleural effusion as an M descriptor. In addition, it is suggested that T2b N0 M0 cases be moved from stage IB to stage IIA, T2a N1 M0 cases from stage IIB to stage IIA, and T4 N0-1 M0 cases from stage IIIB to stage IIIA.
2
4. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994; 330(3):153-158.
1 60 Randomized trial to test the value of induction chemotherapy in resectable IIIA disease. Compared preoperative chemotherapy plus surgery with surgery alone.
Median period of survival was 26 months for chemotherapy plus surgery compared with 8 months for surgery alone (P<0.001). The rate of recurrence was 56% in the group
treated with chemotherapy plus surgery and 74% in the group treated with surgery alone. The prevalence of mutated K-ras oncogenes
was 15% in the group treated with
preoperative chemotherapy and 42% among those treated with surgery alone (P=0.05). Preoperative chemotherapy increases the
5. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994; 86(9):673-680.
1 60 Prospective, randomized study of patients with previously untreated, potentially resectable clinical stage IIIA NSCLC to compare the results of perioperative chemotherapy and surgery with those of surgery alone.
Patient’s treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone (P<.008 by log-rank test; P<.018 by Wilcoxon test). The estimated 2-year and 3-year survival rates were 60% and 56% for the perioperative chemotherapy patients and 25% and 15% for those who had surgery alone, respectively. Perioperative chemotherapy and surgery was more effective than surgery alone.
2
6. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17(9):2692-2699.
1 320 Prospective, randomized study to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy improves survival in unresectable stage III NSCLC.
The median survival duration was better in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P=.03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P=.0001). In selected patients with
unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.
7. Komaki R, Seiferheld W, Ettinger D, Lee JS, Movsas B, Sause W. Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04. Int J Radiat Oncol Biol Phys 2002; 53(3):548-557.
1 163 Prospective, randomized study to evaluate further the toxicity and efficacy of two different strategies of chemo-RT evaluated in two prior Radiation Therapy Oncology Group (RTOG) Phase II studies. 81 patients were treated in Arm 1 and 82 patients in Arm 2.
Incidence of acute esophagitis was higher in Arm 2 than Arm 1 (P<0.0001).
Incidence of acute hematologic toxicity was higher in Arm 1 (P=0.01 for anemia and P=0.03 for other hematologic toxicities) than Arm 2.
Analysis of late toxicity showed that chronic esophageal toxicity was significantly more frequent in Arm 2 than in Arm 1 (P=0.003). The time to in-field progression was
significantly different (P 0.009), favoring Arm 2 compared with Arm 1 (26% vs 45% with failure in 2 years and 30% vs 49% with failure in 4 years, respectively).
The median 2-year and overall 5-year survival rates were similar between the two arms.
Concurrent chemotherapy and hyperfractionated RT resulted in a significant prolongation of the time to in-field progression, but with higher acute and chronic esophagitis.
1
8. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980; 45(11):2744-2753.
1 365 Preliminary analysis of a prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung.
Data suggest patients treated with 5000 or 6000 rad have a better response, tumor control, and survival rate than those receiving lower doses. Patients with high performance status or with tumors in earlier stages have a 2-year survival rate of approximately 40%, in comparison with 20% for other patients. Additional follow-up of patients needed.
2
9. Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B, Pajak TF. A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy
1 848 (n=350
eligible for CALGB
84-33)
Randomized trial to determine maximum tolerated dose of hyperfractionated RT and tumor control over a range of doses: 1.2 Gy/fx BID to doses of 60 Gy, 64.8 Gy, 69.6 Gy, 74.4 Gy, and 79.2 Gy.
Risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among Cancer and Leukemia Group B (CALGB) 84-33 eligible patients, significant incurrence survival for 69.6 Gy group vs <69.6 Gy when analyzed by dose received. No further
10. Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous,
hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiother Oncol 1999; 52(2):137-148.
1 563 Randomized comparison of continuous hyperfractionated accelerated RT with conventional RT. CHART (54 Gy/36 fractions over 12 days (1.5 Gy TID) vs conventional (60 Gy/30 fractions over 6 weeks (2 Gy daily).
In the subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20%-33% (P=0.0007) and a 27% reduction in the relative risk of local progression (P=0.012). In squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P=0.025) and 24% reduction in the relative risk of metastasis (P=0.043). Analysis of mature data confirms that CHART is superior to conventional RT in achieving local tumor control and survival in locally advanced NSCLC.
1
11. Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 58(4):1258-1267.
3b 41 Comparative study to examine dosimetric improvements with respect to tumor-dose conformity and normal tissue sparing using IMRT vs 3D conformal RT (3D-CRT) for advanced-stage NSCLC.
Using IMRT, the median absolute reduction in the percentage of lung volume irradiated to >10 and >20 Gy was 7% and 10%, respectively. This corresponded to a decrease of >2 Gy in the total lung mean dose and of 10% in the risk of radiation pneumonitis. The volumes of the heart and esophagus irradiated to >40-50 Gy and normal thoracic tissue volume irradiated to >10-40 Gy were reduced using the IMRT plans. A marginal increase occurred in the spinal cord maximal dose and lung volume >5 Gy in the IMRT plans, which could be have resulted from the significant increase in monitor units and thus leakage dose in IMRT.
12. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2007; 68(1):94-102.
3c 68 patients
treated with IMRT 222 patients had 3D-CRT
Retrospective study to examine the rate of high-grade treatment-related pneumonitis in patients with advanced NSCLC treated with concurrent chemotherapy and IMRT.
Median follow-up durations for IMRT and 3D-CRT patients were 8 months and 9 months, respectively. The median IMRT and 3D-CRT doses were 63 Gy. The median gross tumor volume was 194 mL for IMRT, compared with 142 mL for 3D-CRT (P=0.002). Despite the IMRT group’s larger gross tumor volume, the rate of grade ≥3 treatment-related pneumonitis at 12 months was 8% compared with 32% for 3D-CRT (P=0.002). Study concludes that in advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of grade ≥3 treatment-related pneumonitis compared with 3D-CRT.
2
13. Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 2008; 87(1):17-23.
3a 55 Retrospective review of patients with stage I-IIIB inoperable NSCLC treated with IMRT.
For median follow-up of 26 months, the 2-year local control and overall survival rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. IMRT treatment resulted in promising outcomes for inoperable NSCLC patients.
3
14. Bush DA, Slater JD, Shin BB, Cheek G, Miller DW, Slater JM. Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest 2004; 126(4):1198-1203.
4 68 Prospective phase II trial to determine the efficacy and toxicity of high-dose
hypofractionated proton beam RT for patients with clinical stage I lung cancer.
The 3-year local control and disease-specific survival rates were 74%, and 72%,
respectively. There was significant
improvement in local tumor control in T1 vs T2 tumors (87% vs 49%), with a trend toward improved survival. Cox regression analysis revealed that patients with higher performance status, female gender, and smaller tumor sizes had significantly improved survival.
15. Nihei K, Ogino T, Ishikura S, Nishimura H. High-dose proton beam therapy for Stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006; 65(1):107-111.
3a 37 To retrospectively study the safety and efficacy of high-dose proton beam therapy for stage I NSCLC.
Patient characteristics (number of patients) were as follows: Stage IA/IB 17/20; medically inoperable/refusal of surgery 23/14; total dose 70/80/88/94; Gy(E) 3/17/16/1. With a median follow-up period of 24 months, the 2-year local progression-free and overall survival rates were 80% and 84%, respectively. The 2-year locoregional relapse-free survival rates in stage IA and stage IB were 79% and 60%,
respectively. Proton beam therapy is a promising treatment modality.
3
16. Chang J, Komaki R, Wen HY, et al. Toxicity and Patterns of Failure of Adaptive/Ablative Proton Therapy for Early-Stage, Medically Inoperable Non-Small Cell Lung Cancer. Int J Rad Oncol Biol Phys 2010:In press.
2 18
To analyze the toxicity and patterns of
failure of proton therapy given in ablative
doses for medically inoperable early-stage
NSCLC.
At a median follow-up time of 16.3
months (range, 4.8-36.3 months), no
patient had experienced grade 4 or 5
toxicity. The most common adverse effect
was dermatitis (grade 2, 67%; grade 3,
17%), followed by grade 2 fatigue (44%),
grade 2 pneumonitis (11%), grade 2
esophagitis (6%), and grade 2 chest wall
pain (6%). Rates of local control were
88.9%, regional lymph node failure
11.1%, and distant metastasis 27.8%.
Twelve patients (67%) were still alive at
the last follow-up; five had died of
metastatic disease and one of preexisting
cardiac disease.
2
17. Shioyama Y, Tokuuye K, Okumura T, et al. Clinical evaluation of proton radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003; 56(1):7-13.
2 51 To evaluate the clinical results of proton RT for patients with NSCLC.
5-year overall survival rate was 29% for all patients, 70% for 9 stage IA patients, and 16% for 19 stage IB patients, respectively (IA vs IB: P< 0.05). The 5-year in-field local control rate was higher in patients with stage IA (89%) when compared with those with stage IB (39%). 47 patients (92%) experienced acute lung toxicity of grade 1 or less; 3 had grade 2, 1 had grade 3, and none experienced grade 4 or higher. Proton therapy is safe and effective treatment.
18. Chang JY, Komaki R, Bucci MK, et al. Failure Patterns and Toxicity of Concurrent Proton Therapy and Chemotherapy for Stage III Non–small Cell Lung Cancer. International journal of radiation oncology, biology, physics 2009; 75(3):S446-S447.
2 42 Analyze failure patterns, survival, and toxicity in a phase II study of patients with stage III NSCLC treated with dose escalated proton therapy and concurrent chemotherapy.
Rates of isolated local failure in the planned target volume (PTV) and in regional lymph nodes outside the PTV were both 13.3%; rate of distant metastasis was 20%; rate of distant metastasis + local/regional failure was 16.7%. Dose-escalated concurrent proton therapy and chemotherapy seems to improve local control with less toxicity than photon therapy. Longer follow-up is needed.
2
19. Widesott L, Amichetti M, Schwarz M. Proton therapy in lung cancer: clinical outcomes and technical issues. A systematic review. Radiother Oncol 2008; 86(2):154-164.
7 17 reports
2 researchers
Systematic review to determine whether proton therapy has a role in the treatment of NSCLC, to assess its safety and efficacy and to evaluate major technical issues related to this technique.
Limited data available for use of proton therapy in clinical practice. Application of proton therapy to lung cancer presents technical challenges. Because of the small number of institutions involved in the treatment of this disease, number of patients, and methodological weaknesses of the trials it is therefore not possible to draw definitive conclusions about the superiority of proton therapy with respect to the photon techniques currently available for the treatment of NSCLC.
3
20. Dillman RO, Herndon J, Seagren SL, Eaton WL, Jr., Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996; 88(17):1210-1215.
1 155 Present long-term survival results based on a median follow-up of more than 8 years for patients enrolled in CALGB 8433 trial. A randomized trial of induction chemotherapy plus high dose radiation vs radiation alone in stage III NSCLC.
Rate of tumor response was 56% for the chemotherapy-RT group and 43% for the RT group (P=.092). After more than 7 years of follow-up, the median survival remains greater for the chemotherapy-RT group (13.7 months) than for the RT group (9.6 months) (P=.012). The percentages of patients surviving after years 1 through 7 were 54%, 26%, 24%, 19%, 17%, 13%, and 13% for the chemotherapy-RT group and 40%, 13%, 10%, 7%, 6%, 6%, and 6% for the RT group. Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before RT have a 4.1-month increase in median survival.
21. Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung Cancer 1994; 10 Suppl 1:S239-244. 1 353 (177 had RT alone and 176 had combined treatment)
Randomized study comparing RT alone to combined RT and chemotherapy in
unresectable squamous cell and large cell lung carcinoma.
2-year survival rate was 14% for patients receiving RT vs 21% for patients receiving the combined treatment (P=0.02). The distant metastasis rate was significantly lower in the group receiving the combined treatment (P<0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively) and remains a major problem in locally advanced NSCLC.
1
22. Sause W, Kolesar P, Taylor SI, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 2000; 117(2):358-364.
1 458 Randomized study to determine if chemotherapy followed by RT resulted in superior survival to either hyperfractionated radiation or standard radiation in surgically unresectable NSCLC.
Overall survival was superior for
chemotherapy and RT. The twice-daily RT arm was not superior in survival for those patients receiving standard radiation. Median survival for standard radiation was 11.4 months; for chemotherapy and irradiation, 13.2 months; and for hyperfractionated irradiation, 12 months. The respective 5-year survivals were 5% for standard RT, 8% for chemotherapy followed by RT, and 6% for hyperfractionated irradiation.
1
23. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 1992; 326(8):524-530.
1 331 To examine effects of concomitant cisplatin and RT on inoperative NSCLC. Randomly assigned patients with nonmetastatic inoperable NSCLC to one of three treatments: RT for 2 weeks (3 Gy given 10 times, in 5 fractions a week), followed by a three-week rest period and then RT for two more weeks (2.5 Gy given 10 times, five fractions a week); RT on the same schedule, combined with 30 mg of cisplatin per square meter of body-surface area, given on the first day of each treatment week; or RT on the same schedule, combined with 6 mg of cisplatin per square meter, given daily before RT.
Survival was improved in the RT-daily-cisplatin group vs RT group (P=0.009): survival in the RT-daily-cisplatin group was 54% at one year, 26% at two years, and 16% at three years, as compared with 46%, 13%, and 2% respectively, in the RT group. Survival in the RT-weekly-cisplatin group
was intermediate (44%, 19%, and 13%) and not significantly different from survival in either of the other two groups.
Survival without local recurrence was 59% at one year and 31% at two years in the RT-daily-cisplatin group; 42% and 30%, respectively, in the RT-weekly-cisplatin group; and 41% and 19%, respectively, in the RT group.
24. Wolf M, Hans K, Becker H, et al. Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced non-small cell lung cancer. Semin Oncol 1994; 21(3 Suppl 4):42-47.
1 85 Randomized, multicenter study to compare RT alone vs chemotherapy with
ifosfamide/vindesine followed by RT in unresectable locally advanced NSCLC.
Of the patients receiving chemotherapy, 25% had a partial remission after 2-cycles, 46% showed no change, and 29% had progressive disease. After RT, response rates were 49% in Arm A and 58% in Arm B, including a 10% complete remission rate in both groups. Median survival was 9 months vs 13.7 months and 2-year survival was 12% vs 24%, both in favor of the group receiving chemotherapy. Results indicate that chemotherapy is able to prolong survival.
1
25. Ansari R, Tokars R, Fisher W, et al. A phase III study of thoracic irradiation with or without concomitant cisplatin in locoregional unresectable non-small cell cancer. A Hoosier Oncology Group Protocol. Proc Am Soc Clin Oncol 1991; 10:241.
1 215 A Phase III study of thoracic irradiation with and without concomitant Cisplatin in locally advanced NSCLC; a Hoosier Oncology Group study.
Overall response rate was 50% on the
combination arm vs 38% on the RT-alone arm. The median progression-free survival time was 23 vs 22 weeks, respectively (P=.0537). The median survival time was 43 weeks on the combination arm vs 46 weeks on the RT arm. The 1-, 2-, and 5-year survival rates were 43%, 18%, and 5% on the combination arm vs 45% 13%, and 2% on the RT arm, respectively. Cisplatin, administered every 3 weeks, does not significantly improve response rate,
progression-free survival, or overall survival when added to thoracic RT for locally advanced unresectable NSCLC.
1
26. Mattson K, Holsti LR, Holsti P, et al. Inoperable non-small cell lung cancer: radiation with or without chemotherapy. Eur J Cancer Clin Oncol 1988; 24(3):477-482.
1 238 Randomized, multicentre study of split-course RT, with or without combination chemotherapy in patients with inoperable NSCLC.
No significant difference was apparent between the RT and the RT-chemotherapy arms with respect to objective response rates (CR + PR) (44% and 49%, respectively), median duration of response (278 and 320 days), local failure (31% and 20%), distant progression (23% and 20%) or median survival (311 and 322 days). The survival figures showed an almost significant (P=0.05) therapeutic advantage of the combined regimen with stage IIIM0 disease. Progressive disease was the cause of death in 92% and 88%. Chemotherapy did not
27. Morton RF, Jett JR, McGinnis WL, et al. Thoracic radiation therapy alone compared with combined chemoradiotherapy for locally unresectable non-small cell lung cancer. A randomized, phase III trial. Ann Intern Med 1991; 115(9):681-686.
1 114 Randomized, multicenter phase III trial. Thoracic RT alone compared with combined chemo-RT for locally advanced resectable NSCLC.
31/ 56 patients treated with combination therapy and 37/58 treated with radiation only had major clinical responses. The median time to progression was 192
days with RT only compared with 199 days for combined modality therapy.
The median survival time was 313 days compared with 317 days, respectively. The 1-, 2-, and 5-year survival rates after
thoracic radiation only were 45% and 7%. With chemo-RT, the survival rates were 46%, 21%, and 5%, respectively.
1
28. Robinow JS, Shaw EG, Eagan RT, et al. Results of combination chemotherapy and thoracic radiation therapy for unresectable non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 1989; 17(6):1203-1210.
1 126 Results of combination chemotherapy and thoracic RT for unresectable NSCLC from a prospective, randomized trial.
Median and 5-year survivals for the group were 14 months and 10%, respectively; for the evaluable subgroup (102 patients), they were 14.8 months and 12%, respectively. Median and 5-year survivals were 16.2 months and 18%, respectively, with VP-16 plus CAP (cytoxan, adriamycin, and cisplatin) plus thoracic RT. Data suggest combined treatment with V-CAP and thoracic RT yielded excellent results.
1
29. Trovo MG, Minatel E, Veronesi A, et al. Combined radiotherapy and chemotherapy versus radiotherapy alone in locally advanced epidermoid bronchogenic carcinoma. A randomized study. Cancer 1990; 65(3):400-404.
1 111 Randomized study comparing combined RT and chemotherapy vs RT alone in locally advanced epidermoid bronchogenic carcinoma.
Difference in response rate was not significant. Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. Study found no significant superiority of combined RT and chemotherapy treatment over RT alone.
1
30. Groen HJ, van der Leest AH, Fokkema E, et al. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol 2004; 15(3):427-432.
1 160 Randomized, multicenter phase 3 trial to determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable NSCLC.
Median survival in the combination arm was 11.8 months and in the RT alone arm 11.7 months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P=0.28)]. Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall
31. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311(7010):899-909.
7 9,387 Meta-analysis using available randomized trials to evaluate the effect of cytotoxic
chemotherapy on survival in patients with NSCLC.
Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at 5-years).
Trials comparing radical RT with radical RT plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death; absolute benefit of 4% at 2-years). Trials comparing supportive care with
supportive care plus chemotherapy 0.73 (27% reduction in the risk of death; 10% improvement in survival at 1-year).
1
32. Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer 1995; 76(4):593-601.
7 1,887 Meta-analysis study using clinical trials that evaluated combined RT plus chemotherapy vs RT alone in patients with stages IIIa and IIIb NSCLC.
For the cisplatin-based group, the estimated pooled odds ratio of death at 1 year and 2 years was 0.76 (0.6-0.9 CI) and 0.70 (0.5-0.9 CI), with a reduction in mortality of 24% and 30%, respectively.
For the noncisplatin-based group, the estimated pooled odds ratio at 1 and 2 years was 1.05 (0.7-1.5 CI) and 0.82 (0.5-1.3 CI), with a reduction in mortality of 5% and 18%, respectively.
1
33. Auperin A, Le Pechoux C, Pignon JP, et al. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 2006; 17(3):473-483.
7 1,764 Meta-analysis based on individual patient data from published and unpublished randomized trials which compared RT alone with the same RT combined with concomitant cisplatin- or carboplatin-based chemotherapy.
The hazard ratio of death among patients treated with radio chemotherapy compared to RT alone was 0.89 (95% CI: 0.81-0.98; P=0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone.
34. Bonner JA, McGinnis WL, Stella PJ, et al. The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study. Cancer 1998; 82(6):1037-1048.
1 99 Randomized trial to compare response rates, distant progression, and survival for patients with unresectable (stage IIIA or IIIB) NSCLC treated with standard fractionated thoracic radiotherapy (SFTRT) vs accelerated hyperfractionated thoracic radiotherapy (AHTRT) with or without combination etoposide and cisplatin chemotherapy.
The improvement in survival associated with AHTRT (with or without chemotherapy) was statistically significant for the subgroup of patients with non-squamous cell carcinoma after adjustment for other potentially
confounding factors (P =0.02). No differences in freedom from systemic progression or survival were found in a comparison of AHTRT with chemotherapy and AHTRT without chemotherapy. Results suggest that treatment of stage IIIA or IIIB NSCLC with AHTRT with or without chemotherapy may improve freedom from local progression and survival as compared with SFTRT. Statistical powers to detect the observed differences in median time to local progression and survival were approximately 55% and 35%,
respectively.
1
35. Schild SE, Stella PJ, Geyer SM, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 54(2):370-378.
1 234 Randomized, multicenter, Phase III trial to determine whether chemotherapy plus BID or q.d. RT resulted in superior survival for patients with stage III NSCLC.
Incidence of severe (≥grade 3) acute
nonhematologic toxicity (q.d. RT, 53% vs BID RT, 65%) and severe (≥grade 3) hematologic toxicities (thrombocytopenia, 41% q.d. RT vs 39% BID RT; neutropenia, 80% q.d. RT vs 81% BID RT) was not significantly different between the treatment arms. No significant differences were found between the q.d. and BID RT arms in terms of time to progression (P=0.9; median 9.4 and 9.6 months,
respectively), overall survival (P=0.4; median 14 and 15 months and 2-year survival rate 37% and 40%, respectively), and cumulative incidence of local failure (P=0.6; 2-year rate 45% and 41%, respectively). Split-course BID RT plus etoposide and cisplatin was not superior to standard q.d. RT plus etoposide and cisplatin. The toxicity, tumor control, and survival rates were similar with either BID or q.d. RT.
36. Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01. J Clin Oncol 2005; 23(10):2145-2154.
1 242 Randomized, multicenter trial to determine the ability of cytoprotectant, amifostine (AM), to reduce chemo-RT-induced esophagitis and evaluate its influence on quality of life and swallowing symptoms.
AM resulted in increased acute nausea, vomiting, cardiovascular toxicity, and infection or febrile neutropenia. The rate of ≥ grade 3 esophagitis was 30% with AM vs 34% without AM.
1
37. Fournel P, Robinet G, Thomas P, et al. Randomized Phase III Trial of Sequential Chemoradiotherapy Compared With Concurrent Chemoradiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 2005; 23(25):5910-5917.
1 205 Randomized Phase III trial to compare the survival impact of concurrent vs sequential treatment with RT and chemotherapy in locally advanced NSCLC.
6 toxic deaths in sequential arm and 10 in concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm. Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%,
respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% vs 3%). Study suggests concurrent chemoradiation is the optimal strategy in locally advanced NSCLC.
1
38. Curran WJ, Jr., Scott C, Langer C, et al. Phase III Comparison of Sequential vs Concurrent Chemoradiation for Patients (Pts) with Unresected Stage III Non-Small Cell Lung Cancer (NSCLC): Initial Report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 2000; 19:(abstr 1891).
1 597 Phase III trial comparing two concurrent chemotherapy and thoracic RT regimens to a standard sequential chemotherapy and thoracic RT approach in patients with unresected stage III NSCLC.
Rates of grade 3-4 non-hematologic toxicity rates were higher with concurrent than sequential therapy, but late toxicity rates were similar. No difference in grade 5 toxicity rates is noted. Preliminary survival results for the concurrent platinum-based chemotherapy and daily thoracic RT arm are quite promising.
1
39. Rolland E, Le Pechoux C, Curran WJ, et al. Concomitant Radio-chemotherapy (CT-RT) versus Sequential CT-RT In Locally Advanced Non-Small-Cell Lung Cancer (NSCLC): A Meta-Analysis Using Individual Patient Data (IPD) From Randomised Clinical Trials (RCTs). Int J Rad Oncol Biol Phys 2007; 69(suppl 3):S5.
7 1,307 patients from
7 trials
Meta-analysis of randomized controlled trials that compared concomitant chemotherapy-RT with sequential chemotherapy-RT.
Concomitant chemotherapy-RT, as compared to sequential chemotherapy-RT, improved survival of patients with locally advanced NSCLC, mainly due to the decrease of loco-regional progression, at the cost of increased acute esophageal toxicity.
40. Vokes EE, Herndon JE, II, Kelley MJ, et al. Induction Chemotherapy Followed by Chemoradiotherapy Compared With Chemoradiotherapy Alone for Regionally Advanced Unresectable Stage III Non-Small-Cell Lung Cancer: Cancer and Leukemia Group B. J Clin Oncol 2007; 25(13):1698-1704.
1 366 Randomized study to determine whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival. Patients were randomly assigned to arm A (immediate concurrent
chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest RT ) or arm B (2 cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy).
Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P=.3), with a median survival on arm A of 12 months vs. 14 months on arm B and a 2-year survival of 29% and 31%. Addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone.
2
41. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol 2003; 21(10):2004-2010.
4 83 To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB NSCLC.
Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019.
2
42. Mina LA, Neubauer MA, Ansari RH, et al. Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023--Updated results. J Clin
1 243 To present updated results from a previously reported randomized phase III trial comparing cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel in patients with inoperable stage III NSCLC.
Updated results confirm prior conclusion that consolidation docetaxel does not improve survival following EP/XRT, is associated with significant toxicities and can no longer be considered as standard treatment for patients with inoperable stage III NSCLC.
43. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009; 374(9687):379-386.
1 396 Phase III trial to compare concurrent chemotherapy and RT followed by resection with standard concurrent chemotherapy and definitive RT without resection.
In group 1, 16 (8%) deaths were treatment related vs four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, vs chemotherapy plus RT. Chemotherapy plus RT with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) NSCLC.
2
44. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2):123-132.
1 731 To determine whether erlotinib prolongs survival in lung cancer after the failure of first-line or second-first-line chemotherapy.
Erlotinib can prolong survival. 1
45. Ramalingam SS, Dahlberg SE, Langer CJ, et al. Outcomes for Elderly, Advanced-Stage Non Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 2008; 26(1):60-65.
3b 224 elderly
patients
To retrospectively analyze Eastern Cooperative Oncology Group (ECOG) 4599 to determine the outcome for elderly patients. According to ECOG 4599, bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) improves survival for advanced, nonsquamous NSCLC.
For elderly patients, there was a trend towards higher response rate (29% vs 17%; P=.067) and progression-freesurvival (5.9 vs 4.9 months; P=.063) with PCB compared withPC, although overall survival (PCB = 11.3 months; PC = 12.1months; P=.4) was similar. Grade 3 to 5 toxicities occurredin 87% of elderly patients with PCB vs 61% with PC (P<.001), with seven treatment-related deaths in the PCB arm comparedwith two with PC.
PCB was associated with a higherdegree of toxicity, but no obvious improvement in survival comparedwith PC.
2
46. Kelly K, Chansky K, Gaspar LE, et al. Phase III Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage III Non-Small-Cell Lung Cancer: SWOG S0023. J Clin Oncol 2008; 26(15):2450-2456.
1 243 Randomized phase III trial to evaluate gefitinib (G) in a maintenance setting in stage III disease following definitive treatment.
For median follow-up time of 27 months, median survival time was 23 months for gefitinib (n=118) and 35 months for placebo (n=25; two-sided P=.013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. Gefitinib did not improve survival. Decreased survival was due to cancer not gefitinib toxicity.
1
47. Blumenschein G, Moughan J, Curran WJ, et al. A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (pts)
4 87 Phase II trial testing the combination of C225 with CRT in unresectable stage III NSCLC with planned sample size of 84 patients.
Response rate is 62% (n=54) and 12 month overall survival is 68%. Adverse events related to treatment include 20% of patients with grade 4 hematologic toxicities and 7 patients who had
48. Govindan R, Bogart J, Wang X, Hodgson L, Kratzke R, Vokes EE. Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407. J Clin Oncol 2009; 27(15s):(suppl; abstr 7505).
2 99 Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable NSCLC.
The most common histological type was adenocarcinoma (46% in Arm A and 41% in Arm B). Updated toxicity data (grade 3 or greater, %) by arms (arm A/arm B) for 106 patients: neutropenia 40/47; febrile neutropenia 8/6, thrombocytopenia 36/34, nausea/vomiting 8/10, esophagitis 32/24, skin rash 2/21 and fatigue 22/17. The median follow up time is 17 months. Preliminary efficacy data by arms (arm A/arm B) for 99 patients: complete or partial response 73% (95% CI 59-83)/71% (95% CI 57-81%), median failure free survival (months) 12.9 (95% CI 8.6-18.0)/10.3 (95% CI 8.7-18.9); 18 month survival 57% (95% CI 41-79)/47% (95% CI 33-67) and median survival (months) 22.3/18.7. Combination of
pemetrexed, carboplatin and thoracic radiation meet the protocol-specified criteria for further study.
2
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(7):1623-1631.
3a 245 Retrospective evaluation of stereotactic hypofractionated high-dose irradiation for stage I non-small-cell lung carcinoma.
Hypofractionated high-dose STI with BED <150 Gy was good for curative treatment of patients with stage I NSCLC.
Local control and survival rates were better with BED ≥100 Gy compared with <100 Gy.
Survival rates in medically operable, BED
≥100 Gy were excellent.
2
50. 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(30):4833-4839.
4 70 Prospective phase 11 trial using stereotactic body radiation therapy (SBRT) in medically inoperable early-stage lung cancer.
Kaplan-Meier local control at 2 years was 95%. Median survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. Achieved high rates of local control.
2
51. Simon CJ, Dupuy DE, DiPetrillo TA, et
52. Steinke K, Sewell PE, Dupuy D, et al. Pulmonary radiofrequency ablation--an international study survey. Anticancer Res 2004; 24(1):339-343.
15 7 centers
reported 493 percutaneous procedures
Retrospectively survey experiences of 14 centers on use of percutaneous pulmonary radiofrequency ablation.
Percutaneous pulmonary radiofrequency ablation is a safe, minimally invasive tool for local pulmonary tumor control with little mortality and morbidity, short hospital stay and gain in quality of life.
2
53. Yoshimatsu R, Yamagami T, Terayama K, Matsumoto T, Miura H, Nishimura T. Delayed and recurrent pneumothorax after radiofrequency ablation of lung tumors. Chest 2009; 135(4):1002-1009.
3c 68 Retrospective study to examine the rate of delayed or recurrent pneumothorax after radiofrequency ablation for lung tumors and the risk factors associated with its occurrence. Study was based on 194 consecutive sessions of percutaneous radiofrequency ablation of 220 lung tumors.
Pneumothorax after radiofrequency ablation occurred in 82/194 ablation sessions (42.3%). 33/82 sessions had either delayed
pneumothorax (n=20) or recurrent pneumothorax (n=13). Results showed that delayed or recurrent pneumothorax is relatively frequently encountered after radiofrequency ablation of lung tumors.