Lung Cancer and Postoperative Radiotherapy

Transcription

1 . Fernando HC, Goldstraw P. The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by postsurgical pathologic staging. Cancer 990; 65(): Keller SM, Adak S, Wagner H, Johnson DH. Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg 000; 70():58-65; discussion Postoperative radiotherapy in non-smallcell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 998; 5(94): Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. The Lung Cancer Study Group. N Engl J Med 986; 5(): Evaluated accuracy of clinical evaluative thoracic staging versus postsurgical pathological staging. 9 7 stage II and III 7 9 trials,8 patients Comparison of the extent of mediastinal dissection on staging and survival in patients enrolled in a clinical trial that evaluated chemotherapy in addition to PORT in resected stage II and III patients. A systematic review and meta-analysis of the available evidence from randomized trials of PORT. 0 Randomized trial to evaluate effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. Preoperative evaluation underestimated far more commonly than it overestimated. Mediastinal node involvement was not overestimated since any suggestion of such involvement was confirmed by mediastinal exploration. Thus, a major aspect of preoperative evaluation is the exclusion of gross mediastinal gland involvement by mediastinal exploration. Among the 87 patients who underwent systematic sampling, N disease was identified in 40%, N disease in 60%. This was not significantly different than the 86 patients who underwent complete mediastinal lymph node dissection. Among the patients with N metastases, multiple levels of N disease were documented in 0% of patients who underwent complete mediastinal lymph node dissection and in % of patients who had systematic sampling (P=0.00). Median survival was 57.5 months for those patients who had undergone complete mediastinal lymph node dissection and 9. months for those patients who had systematic sampling (P=0.004). However, the survival advantage was limited to patients with right lung tumors (66.4 months vs 4.5 months, P<0.00). PORT is detrimental to patients with earlystage completely resected NSCLC and should not be used routinely for such patients. The role of PORT in the treatment of N tumors is not clear and may warrant further research. No evidence that RT improved survival. Overall recurrence rates were reduced by RT in patients with N disease (P<0.05). RT can reduce local recurrences after resection of epidermoid carcinoma of the lung, but does not increase survival rates. * See Last Page for Key 00 Review Decker/Langer Page

2 5. Dautzenberg B, Arriagada R, Chammard AB, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'etude et de Traitement des Cancers Bronchiques. Cancer 999; 86(): Debevec M, Bitenc M, Vidmar S, et al. Postoperative radiotherapy for radically resected N non-small-cell lung cancer (NSCLC): randomised clinical study Lung Cancer 996; 4(): Lafitte JJ, Ribet ME, Prevost BM, Gosselin BH, Copin MC, Brichet AH. Postresection irradiation for T N0 M0 non-small cell carcinoma: a prospective, randomized study. Ann Thorac Surg 996; 6(): Stephens RJ, Girling DJ, Bleehen NM, Moghissi K, Yosef HM, Machin D. The role of post-operative radiotherapy in nonsmall-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T-, N-, M0 disease. Medical Research Council Lung Cancer Working Party. Br J Cancer 996; 74(4): Van Houtte P, Rocmans P, Smets P, et al. Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design. Int J Radiat Oncol Biol Phys 980; 6(8): stage I 80 stage II 7 stage III 74 9 ptn 54 ptn ptn 6 TN0M0 60 irradiated 08 T-N- Randomized evaluation of PORT of patients with completely resected NSCLC (60 Gy). Randomized evaluation of PORT (0 Gy/ weeks) in pt-n patients. Randomized evaluation of PORT in T node negative patients: to see if more locoregional malignant sites are overlooked in T N0 M0 than in T, and if T N0 cancer might benefit from postresection irradiation. To compare surgery alone with surgery plus PORT in patients with pathologically staged T- N- M0 NSCLC (40 Gy/ weeks with posterior spinal cord block). 4 To test postoperative supervoltage RT in a controlled trial to evaluate level of improvement for patients with bronchogenic carcinoma. Five-year OS was 4% for the control group and 0% for the RT group. RT had no significant effect on local recurrence. The rate of non-cancer deaths rose with dose per fraction. Five-year survival rates did not show statistically significant differences between the irradiated and surgically treated patients only with respect to sex, ptnm stage, histology and frequency of locoregional failure. The number of metastatic mediastinal lymph nodes was the only significant prognostic factor (P<0.005) in both randomized groups. No significant difference in survival at 5 years (5.% vs 5.6%, RT vs no RT). No difference considering cell type or irradiation, either in the survival or in the mode of recurrence. No difference in survival or pattern of recurrence overall. In the N group, no differences between the treatment groups were seen, but in the N group surgery plus PORT patients appeared to gain a one month survival advantage, delayed time to local recurrence and time to appearance of the bone metastases. There is, therefore, no clear indication for PORT in N disease, but the question remains unresolved in N disease. No increase in survival times was noticed in the irradiated group. The 5 year survival rate was lower in this group (4% vs 4% for the control group), but difference is not significant. Analysis shows a detrimental effect of RT in thet group, especially after pneumectomy. The slight benefit from RT was a decrease in local relapse. * See Last Page for Key 00 Review Decker/Langer Page

3 0. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-smallcell lung cancer patients treated with concurrent chemotherapy and intensitymodulated radiotherapy. Int J Radiat Oncol Biol Phys 007; 68(): Trodella L, Granone P, Valente S, et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol 00; 6():-9.. Burdett S, Stewart L. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer 005; 47():8-8.. Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 006; 4(9): von Lieven H, Burkhardt E. Postoperative radiotherapy of NSCLC--outcome after - D treatment planning. Strahlenther Onkol 00; 77(6):0-06. c 68 patients treated with IMRT patients had DCRT Retrospective study to examine the rate of high-grade treatment-related pneumonitis in patients with advanced NSCLC treated with concurrent chemotherapy and IMRT. 04 Randomized trial to evaluate PORT in completely resected stage I patients. 7,8 patients 9 randomized trials Review individual patient data meta-analysis of the effectiveness of PORT in NSCLC. a 7,465 Retrospective study to examine the association between survival and PORT in patients with resected NSCLC. Patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. a 55 stage I-IIIB 5 received PORT 47 did not Comparison of outcome with or without receiving -D PORT. Retrospective review of those who have been treated at the University of Giessen between 986 and 996 by surgery or surgery and -D planned PORT with Gy. Despite the IMRT group s larger gross tumor volume, the rate of grade treatment-related pneumonitis at months was 8% compared with % for DCRT (P=0.00). Study concludes that in advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of grade treatment-related pneumonitis compared with DCRT. Promising trend of a decrease in local recurrence rate (.% vs %) and increased disease-free rate and OS rate at 5 years, (70% vs 60% and 67% vs 58%) with RT. Treatment related toxicity was felt to be acceptable. Results continue to show PORT to be detrimental, with an 8% relative increase in the risk of death. Similar detriments were observed for local recurrence-free survival, distant recurrence-free survival and overall recurrence-free survival. There continues to be evidence that the effects of PORT are more harmful in those patients with stage I disease than those with stage II disease. PORT did not have a significant impact on survival, but for patients with N nodal disease, PORT was associated with a significant increase in survival. For patients with N0 (HR =.76; 95% CI.005 to.76; P=.045) and N (HR =.097; 95% CI.05 to.86; P=.096) nodal disease, PORT was associated with a significant decrease in survival. With individually -D planned PORT there was a lower risk of death in all stages with lymph node metastases. * See Last Page for Key 00 Review Decker/Langer Page

4 5. Wilson EM, Joy Williams F, Lyn BE, Aird EG. Comparison of two dimensional and three dimensional radiotherapy treatment planning in locally advanced non-small cell lung cancer treated with continuous hyperfractionated accelerated radiotherapy weekend less. Radiother Oncol 005; 74(): Machtay M, Lee JH, Shrager JB, Kaiser LR, Glatstein E. Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected nonsmall-cell lung carcinoma. J Clin Oncol 00; 9(9): Wakelee HA, Stephenson P, Keller SM, et al. Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E590. Lung Cancer 005; 48(): Lally BE, Detterbeck FC, Geiger AM, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer 007; 0(4):9-97. c 4 Comparison of D and D calculations of Patients with inoperable NSCLC being treated with continuous hyperfractionated accelerated radiotherapy weekend less. 4 0 Retrospective review to evaluate for excess intercurrent deaths in patients receiving PORT for lung cancer in patients with positive nodes or margins. 488 Comparison of risk of intercurrent disease in treated patients versus age and gender matched controls from U.S. vital statistics. a 6,48 from 7 registries from SEER To investigate whether the mortality from heart disease, a manifestation of intercurrent disease after PORT, has decreased over time for patients with NSCLC. A lower dose to tumor was obtained using D planning due to the method of dose calculation and spinal cord and lung doses were significantly higher. The authors report no statistical increase in intercurrent deaths. Three of 8 intercurrent deaths related to RT complications. The 4 year actuarial risk of intercurrent disease for treated patients at 8 months median survival was.9% compared with an expected risk of 0.% (P=0.6) intercurrent disease increased with age. The risk of intercurrent disease following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or PORT plus four cycles of cisplatin (60 mg/m, day. PORT use was associated with an increase in heart disease mortality (HR,.0; 95% CI,.04-.6; P=.09) along with older age, male sex, African-American race, and earlier year of diagnosis. The association was confirmed in the cohort that was diagnosed from 98 to 988 but not for the cohort that was diagnosed from 989 to 99. The results from this study demonstrated that the risk of heart disease mortality associated with PORT has declined in more recent years. This may be secondary to improvements in the treatment planning and delivery of thoracic RT. * See Last Page for Key 00 Review Decker/Langer Page 4

5 9. Marks LB. A standard dose of radiation for "microscopic disease" is not appropriate. Cancer 990; 66(): Choi NC, Grillo HC, Gardiello M, Scannell JG, Wilkins EW, Jr. Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int J Radiat Oncol Biol Phys 980; 6():-5.. Mayer R, Smolle-Juettner FM, Szolar D, et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest 997; (4): Feng QF, Wang M, Wang LJ, et al. A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys 000; 47(4): Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 000; 4(7):7-. 7 N/A Review the appropriateness of standardizing radiation dosage for microscopic tumors by discussing the factors that determine dosage level. b 48 patients with N, N, T carcinoma 9 received PORT 55 no further treatment Retrospective evaluation of PORT. 55 Randomized trial to evaluate the value of adjuvant postoperative EBRT in patients with radically resected NSCLC pt- pn0- compared to patients with resected NSCLC 66 N and N 8 (S+RT) 8 (S alone) without adjuvant EBRT. Randomized trial compared observation with 60 Gy postoperatively using Linac 6-8 Mv. 488 Randomized trial to determine whether combination chemotherapy plus thoracic RT is superior to thoracic RT alone in prolonging survival and preventing local recurrence in patients with completely resected stage II or IIIa NSCLC. Patients were randomly assigned to receive either four 8-day cycles of cisplatin and etoposide administered concurrently with RT to 50.4 Gy, or RT alone. Since the number of clonogens in an occult site may vary from 0 degrees to 0(8), Ni is the major determinant of the required dose. The intrinsic radiation sensitivity of the clonogens is also extremely important in determining the dose. Regions where clinicoradiologic evaluation is difficult (eg, pelvis and obese neck) require higher doses because macroscopic tumor deposits may exist. Relatively low doses (0 to 0 Gy) are often thought to be inadequate for microscopic tumor. However, similar doses have been reported to sterilize microscopic tumor in ovarian, rectal, bladder, breast, and head and neck carcinomas. Increased survival was found in N+ patients with adenocarcinoma only, with survival rates of 85% and 5% at year, 4% and 8% at 5 years for S+RT and S (surgery only) groups. Most recurrences noted at 50 Gy. The overall 5 year survival rate was 9.7% in the treated group and 0.4% in the observation arm. Decreased local recurrence in the treated group. 5-year OS rate was 4.9% in the S +RT group and 40.5% in the S alone (no further treatment) Group (P= 0.56). Median survival was 9 months in the RT group and 8 months in the RT plus chemotherapy group (P=0.56). The relative likelihood of survival was 0.9 (95% CI 0.74 to.8). Intrathoracic disease recurred within the radiation field in % in the RT group and % in the chemo RT group (P=0.84). * See Last Page for Key 00 Review Decker/Langer Page 5

6 4. Bradley JD, Paulus R, Graham MV, et al. Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG J Clin Oncol 005; (5): Feigenberg SJ, Hanlon AL, Langer C, et al. A phase II study of concurrent carboplatin and paclitaxel and thoracic radiotherapy for completely resected stage II and IIIA non-small cell lung cancer. J Thorac Oncol 007; (4): 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 004; 58(4): a a 88 stage II-IIIA 40 total 7 had T or T 4 N 9 ENE 6 involved surgical margins Determine PFS and OS in completely resected stage II-IIIA who have received concurrent paclitaxel/carboplatin and RT. To determine the feasibility of combining concurrent carboplatin/paclitaxel and thoracic RT for completely resected stage II and IIIA NSCLC. b 4 Comparative study to examine dosimetric improvements with respect to tumor-dose conformity and normal tissue sparing using IMRT vs DCRT for advanced-stage NSCLC. Treatment toxicity was considered acceptable. Median follow-up was 56.7 months. Median overall and PFS was 56. and 5.6 months, respectively. This compared favorably to the ECOG 590 trial. At a median follow up of 7 months, the - and 5-year Kaplan-Meier estimates of local regional control, freedom from distant metastasis, freedom from brain metastasis, and OS were 9% and 88%, 77% and 59%, 87% and 7% and 7% and 44%, respectively. Fourteen patients developed distant metastasis as the initial site of failure, eight of whom had brain metastasis. Brain metastasis was the only site of failure in four of the eight patients. Multivariate regression analysis demonstrated that the only independent predictor of OS was histology (P=0.0). Using IMRT, the median absolute reduction in the percentage of lung volume irradiated to >0 and >0 Gy was 7% and 0%, respectively. This corresponded to a decrease of > Gy in the total lung mean dose and of 0% 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 >0-40 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. * See Last Page for Key 00 Review Decker/Langer Page 6

7 7. Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensitymodulated radiation therapy (IMRT), D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys 00; 57(): Sura S, Gupta V, Yorke E, Jackson A, Amols H, Rosenzweig KE. Intensitymodulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol 008; 87(): Chang JY, Zhang X, Wang X, et al. Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 006; 65(4): Bush DA, Slater JD, Shin BB, Cheek G, Miller DW, Slater JM. Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest 004; 6(4): patients with stage I To systematically evaluate four different techniques of RT used to treat NSCLC and to determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage and achieving dose escalation. a 55 Retrospective review of patients with stage I- IIIB inoperable NSCLC treated with IMRT. 4 5 total histograms 0 stage I 5 stage III To compare dose-volume histograms in patients with NSCLC treated by photon or proton RT 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. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 5%-0% greater than DCRT and 0%-40% greater than elective nodal irradiation. Whereas, the possibility of dose escalation is severely limited with elective nodal irradiation, the potential for pulmonary and esophageal toxicity is clearly increased. For median follow-up of 6 months, the -year local control and OS rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, -year local control and OS rates were 58% and 58%, respectively, with a median survival time of 5 months. IMRT treatment resulted in promising outcomes for inoperable NSCLC patients. For stage I, the mean total lung V5, V0, and V0 were.8%, 4.6%, and 5.8%, respectively, for photon DCRT with 66 Gy, whereas they were.4%,.%, and 0.9%, respectively, with proton with dose escalation to 87.5 cobalt GyE (P=0.00). For stage III, the mean total lung V5, V0, and V0 were 54.%, 46.9%, and 4.8%, respectively, for photon DCRT with 6 Gy, whereas they were 9.7%, 6.6%, and.6%, respectively, for proton with dose escalation to 74 cobalt GyE (P=0.00). In all cases, the doses to lung, spinal cord, heart, esophagus, and integral dose were lower with proton therapy even compared with IMRT. The -year local control and disease-specific survival rates were 74%, and 7%, respectively. There was significant improvement in local tumor control in T vs T 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. * See Last Page for Key 00 Review Decker/Langer Page 7

8 . Hata M, Tokuuye K, Kagei K, et al. Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int J Radiat Oncol Biol Phys 007; 68(): Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I nonsmall cell lung cancer using a regimen of four fractions during week. J Thorac Oncol 007; (0): Koto M, Tsujii H, Yamamoto N, Nishimura H, Yamada S, Miyamoto T. Dosimetric factors used for thoracic X-ray radiotherapy are not predictive of the occurrence of radiation pneumonitis after carbon-ion radiotherapy. Tohoku J Exp Med 007; (): McCaughan BC, Martini N, Bains MS, McCormack PM. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 985; 89(6): Sawyer TE, Bonner JA, Gould PM, et al. Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 997; 64(5):40-407; discussion To present treatment outcomes of hypofractionated high-dose proton beam therapy for stage I NSCLC To determine the local control and 5-year survival rates To analyze the relationship between dosimetric factors developed for X-ray RT and the incidence of radiation pneumonitis in patients with stage I NSCLC after carbon-ion RT. 4 5 total 45 TN0 TN- Evaluation of results of treatment in patients with chest wall invasion who have had complete resection (7 patients). b 4 To determine the effectiveness of PORT in stage IIIA NSCLC according to regression tree analyses of recurrence risks. Regression tree analysis was used to separate patients who had undergone operation alone into groups that had a high, intermediate, or low risk of local recurrence and death. The -year overall and cause-specific survival rates were 74% and 86%, respectively. All but one of the irradiated tumors were controlled during the follow-up period. Five patients showed recurrences 6-9 months after treatment, including local progression and new lung lesions outside of the irradiated volume in and 4 patients, respectively. The local progression-free and disease-free rates were 95% and 79% at years, respectively. No therapy-related toxicity of grade was observed. The patients 5-year lung cancer-specific survival rate was 68% (IA: 87%, IB: 4%). The OS was 45% (IA: 6%, IB: 5%). Half of the deaths were attributable to intercurrent diseases. No toxic reactions in the lung greater than grade were detected. Dosimetric factors useful for predicting radiation pneumonitis in X-ray RT, such as the percentage of the computed tomographydefined total lung volume receiving >5, >0, and >0 GyE, and mean lung dose, were not predictive factors for radiation pneumonitis after carbon-ion RT. The dosimetric factors used for X-ray RT are not applicable for carbon-ion RT in patients with NSCLC. The dosimetric factors for carbon-ion RT remain to be developed. 56% 5 year survival in completely resected TN0 patients without PORT. % 5 year survival in completely resected TN- (/ received PORT). Adjuvant postoperative thoracic RT (compared with operation alone) was associated with an improvement in freedom from local recurrence and survival for patients who had an intermediate or high risk of local recurrence and death. * See Last Page for Key 00 Review Decker/Langer Page 8

9 6. Piehler JM, Pairolero PC, Weiland LH, Offord KP, Payne WS, Bernatz PE. Bronchogenic carcinoma with chest wall invasion: factors affecting survival following en bloc resection. Ann Thorac Surg 98; 4(6): Patterson GA, Ilves R, Ginsberg RJ, Cooper JD, Todd TR, Pearson FG. The value of adjuvant radiotherapy in pulmonary and chest wall resection for bronchogenic carcinoma. Ann Thorac Surg 98; 4(6): Burkhart HM, Allen MS, Nichols FC, rd, et al. Results of en bloc resection for bronchogenic carcinoma with chest wall invasion. J Thorac Cardiovasc Surg 00; (4): Gould PM, Bonner JA, Sawyer TE, Deschamps C, Lange CM, Li H. Patterns of failure and overall survival in patients with completely resected T N0 M0 nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 999; 45(): Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 5 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 995; (700): b b 66 total TN0 completely resected 5 total TN0 completely resected To determine survival characteristics of patients undergoing surgery for tumors involving the chest wall. Evaluation of adjuvant RT in patients with tumors involving the chest wall Review of experience with en bloc lung and chest wall resection for bronchogenic carcinoma. a 9 Retrospective review to determine patterns of failure and OS for patients with completely resected T N0 M0 NSCLC. 7 9,87 patients (7,5 deaths) from 5 randomized controlled trials Meta-analysis of available randomized trials to evaluate the effect of cytotoxic chemotherapy on survival in patients with NSCLC. 6/ received PORT. Reasons for selection of treatment not stated; possible selection bias. No difference in survival with treatment; 5 year survival 5%. 7/9 who received RT survived 5 years. /4 who received no RT survived 5 years. Overall 5-year actuarial survival was 8.7%. Five-year survival for patients with stage IIb disease (T N0 M0) was 44.% compared with only 6.% for those with stage IIIa disease (T N M0 or T N M0, P=.008). Women had a better 5-year survival than men (5.9% vs.0%, P=.0). The best 5-year survival was observed in women with stage IIb disease (6.%). The actuarial - and 4-year OS rates for the entire cohort were 48% and 5%, respectively. The actuarial local control at 4 years was 94%. Neither the type of surgical procedure performed nor the addition of thoracic RT impacted local control or OS. Patients with completely resected T N0 M0 non-small cell lung cancer have similar local control and OS irrespective of primary location, type of surgery performed, or use of adjuvant RT. Additionally, the tumor recurrence rate and OS found in this study support the placement of this group of patients in stage IIB of the 997 AJCC lung staging classification. Results favored chemotherapy in all comparisons and reached conventional levels of significance when used with radical RT and with supportive care. * See Last Page for Key 00 Review Decker/Langer Page 9

10 4. Hamada C, Tanaka F, Ohta M, et al. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in nonsmall-cell lung cancer. J Clin Oncol 005; (): Booth C, Shepherd F. Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancer. Journal of Thoracic Oncology 006; (): Tada H, Tsuchiya R, Ichinose Y, et al. A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pn non-small cell lung cancer (JCOG904). Lung Cancer 004; 4(): Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 00; 95(9): Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg 004; 6(): Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall-cell lung cancer. N Engl J Med 004; 50(4): ,00 Meta-analysis of postoperative tegafur-uracil T 08 trials in Japan. patients T 674 patients 7 N/A Review of published studies of adjuvant chemotherapy for resected NSCLC. 9 pn,09 patients 606 in mitomycin, vindesine and cisplatin group and 60 controls 8 patients 9 received chemotherap y, C group 89 patients no chemo, Comparison of cisplatin/vindesine versus no further treatment after resection in pathologic N patients. Adjuvant Lung Project Italy, a randomized trial to examine the potential benefits of adjuvant chemotherapy for survival. Stage I, II, IIIA NSCLC after complete resection randomized to cycles of mitomycin, vindesine and cisplatin or no further treatment. To run a large randomized trial to confirm the survival benefits seen in the meta-analysis that suggest a survival benefit for cisplatin-based chemotherapy when given in addition to surgery, radical RT or best supportive care. No C group,867 Randomized, multicenter trial to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of NSCLC. Patients were randomly assigned either or 4 cycles of cisplatin-based chemotherapy or to observation. Postoperative adjuvant chemotherapy with tegafur-uracil was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients. Supports use of postoperative chemotherapy in selected patients. Five year OS was 8.% in the treated group and 6.% in the control group (P=0.89). Subset analysis demonstrated improved survival in the ptn0 group, from 75.% to 90.7% with treatment (P<0.05). No statistically significant difference between the groups in OS (HR = 0.96, 95% CI 0.8 to.; P=.589) or PFS (HR = 0.89, 95% CI 0.76 to.0; P=.8). Trial failed to confirm the effectiveness of adjuvant chemotherapy for patients with NSCLC. 98 (5%) of patients have died, but there is currently no evidence of a benefit in OS to the C group: HR.0 (95% CI ), P=0.90). Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (44.5% vs 40.4% at 5 years [469 deaths vs 504]. Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation (9.4% vs 4.% at 5 years [58 events vs 577]. Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected NSCLC. 4 * See Last Page for Key 00 Review Decker/Langer Page 0

11 47. Butts CA, Ding K, Seymour L, et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-0. J Clin Oncol 00; 8(): Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med 005; 5(5): Vincent MD, Butts C, Seymour L, et al. Updated survival analysis of JBR.0: A randomized phase III trial of vinorelbine/cisplatin versus observation in completely resected stage IB and II nonsmall cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts) 009; 7(5S): total patients 9, TN0 6, T- N Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II NSCLC: updated OS analysis of JBR Randomized trial to determine whether adjuvant vinorelbine plus cisplatin prolongs OS among patients with completely resected early-stage NSCLC. Patients were randomly assigned to vinorelbine plus cisplatin or to observation. 48 Report on the updated survival analysis of JBR-0, a randomized phase III trial. Patients with completely resected stage IB (TN0) or II (T-N) NSCLC were randomized to receive 4 cycles of vinorelbine/cisplatin or observation. 7 deaths. Adjuvant cisplatin-based chemotherapy continues to show a benefit (HR 0.78; 95% CI, 0.6 to 0.99; P=.04). There was a trend for interaction with disease stage (P=.09; HR for stage II, 0.68; 95% CI, 0.5 to 0.9; P=.0; stage IB, HR,.0; 95% CI, 0.7 to.5; P=.87). Adjuvant cisplatin-based chemotherapy resulted in significantly prolonged disease-specific survival (HR, 0.7; 95% CI, 0.55 to 0.97; P=.0). Observation was associated with significantly higher risk of death from lung cancer (P=.0), with no difference in rates of death from other causes or second primary malignancies between the arms. OS was significantly prolonged in the chemotherapy group compared with the observation group (94 vs 7 months. 5-year survival rates were 69 % and 54 %, respectively (P=0.0).Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and OS among patients with completely resected earlystage NSCLC. Survival analysis continues to show a benefit for chemotherapy: HR.78 (CI.6-.99, P=.04). Benefit appears to be confined to N patients. There was no increase in death from other causes in the chemotherapy arm. * See Last Page for Key 00 Review Decker/Langer Page

12 50. Strauss GM, Herndon JE, nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 96 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 008; 6(): Mineo TC, Ambrogi V, Corsaro V, Roselli M. Postoperative adjuvant therapy for stage IB non-small-cell lung cancer. Eur J Cardiothorac Surg 00; 0(): Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 006; 7(9): Analysis of Cancer and Leukemia Group B 96, a randomized trial designed for stage IB NSCLC. Patients were randomly assigned to adjuvant chemotherapy or observation. 66 stage IB 840 total patients with stage IB-IIIA NSCLC from 0 centers in 4 countries 4 assigned to observation 407 assigned to 0 mg/m() vinorelbine plus 00 mg/m() cisplatin Comparison of cisplatin and etoposide versus no further treatment after resection in stages IB patients. To compare the effect of adjuvant vinorelbine plus cisplatin vs observation on survival in patients with completely resected NSCLC. Main toxicity were grades to 4 neutropenia; no treatment-related deaths. Survival was not significantly different (HR, 0.8; CI 0.64 to.08; P=.), but analysis showed a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors 4 cm in diameter (HR, 0.69; CI 0.48 to 0.99; P=.04). Adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Statistically significant survival advantage for patients with tumors 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors. The rates of locoregional recurrence and distant metastases were 8% and 0%, respectively, in the adjuvant chemotherapy group and 4% and 4%, respectively, in the control group. Five year OS was 59% in the cisplatin and etoposide group and 0% in the control group (P=0.0). The difference in the Kaplan-Meier survival between the groups was significant as assessed using the log-rank test (P= 0.04). After a median follow-up of 76 months (range 4-6), median survival was 65.7 months (95% CI ) in the chemotherapy group and 4.7 (5.7-5.) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (HR 0.80 [95% CI ]; P=0.07). OS at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). * See Last Page for Key 00 Review Decker/Langer Page

13 5. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 008; 6(): Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA nonsmall-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 008; 7(): The benefit of adjuvant treatment for resected locally advanced non-small-cell lung cancer. The Lung Cancer Study Group. J Clin Oncol 988; 6(): Pisters KM, Le Chevalier T. Adjuvant chemotherapy in completely resected nonsmall-cell lung cancer. J Clin Oncol 005; (4): Dautzenberg B, Chastang C, Arriagada R, et al. Adjuvant radiotherapy versus combined sequential chemotherapy followed by radiotherapy in the treatment of resected nonsmall cell lung carcinoma. A randomized trial of 67 patients. GETCB (Groupe d'etude et de Traitement des Cancers Bronchiques). Cancer 995; 76(5): a 7,465 Retrospective study to examine the association between survival and PORT in patients with resected NSCLC. Patients were selected from the SEER database. c 840 received PORT 64 T-N0- To study the impact of PORT on survival in the Adjuvant Navelbine International Trialist Association randomized study of adjuvant chemotherapy. Comparison of split course RT with or without CAP for patients with positive margins or highest paratracheal node positive. 7 N/A Review of published studies of adjuvant chemotherapy for resected NSCLC. 67 stage I 8 patients stage II 70 patients stage III 89 patients Comparison of 60 Gy with or without Cyclophosphamide/Adriamycin/cisplatin/vincr istine/lomustine. PORT did not have a significant impact on survival, but for patients with N nodal disease, PORT was associated with a significant increase in survival. For patients with N0 (HR =.76; 95% CI.005 to.76; P=.045) and N (HR =.097; 95% CI.05 to.86; P=.096) nodal disease, PORT was associated with a significant decrease in survival. In univariate analysis, PORT had a deleterious effect on the overall population survival. Patients with pn disease had an improved survival from PORT in the observation arm (median survival 5.9 vs 50. months), whereas PORT had a detrimental effect in the chemotherapy group (median survival 9.6 months and 46.6 months). In contrast, survival was improved in patients with pn disease who received PORT, both in the chemotherapy (median survival.8 vs 47.4 months) and observation arm (median.7 vs.7 months). There was a difference in disease free survival in favor of the CAP + RT arm, mainly in the nonsquamous patients. OS trended towards the experimental arm but was not significant (P=0.). Supports use of postoperative chemotherapy in selected patients. There was no difference in disease free or OS. * See Last Page for Key 00 Review Decker/Langer Page

14 58. 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 nonsmall-cell lung cancer. J Clin Oncol 999; 7(9): Randomized phase III study to determine whether concurrent or sequential treatment with RT and chemotherapy improves survival in unresectable stage III NSCLC. Median survival duration was significantly superior in patients receiving concurrent therapy (6.5 months), as compared with those receiving sequential therapy (. months). Two-, -, 4-, and 5-year survival rates in the concurrent group (4.6%,.%, 6.9%, and 5.8%, respectively) were better than those in the sequential group (7.4%, 4.7%, 0.%, and 8.9%, respectively). Concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach. * See Last Page for Key 00 Review Decker/Langer Page 4

15 Table Key Key Numbers -7 are for studies of therapies while numbers 8-5 are used to describe studies of diagnostics.. Randomized Controlled Trial Treatment. Controlled Trial. Observation Study a. Cohort b. Cross-sectional c. Case-control 4. Clinical Series 5. Case reviews 6. Anecdotes 7. Reviews 8. Randomized Controlled Trial Diagnostic 9. Comparative Assessment 0. Clinical Assessment. Quantitative Review. Qualitative Review. Descriptive Study 4. Case Report 5. Other (Described in text) Abbreviations Key DCRT = D-confromal radiation therapy CAP = Cyclophosphamide/Adriamycin/Cisplatin CI = Confidence interval EBRT = External-beam radiation therapy HR = Hazard ratio IMRT = Intensity-modulated radiotherapy NSCLC = Non-small-cell lung cancer OS = Overall survival PFS = Progression-free survival PORT = Postoperative radiotherapy RT = Radiation therapy S = Surgery Key Category - The conclusions of the study are valid and strongly supported by study design, analysis and results. Category - The conclusions of the study are likely valid, but study design does not permit certainty. Category - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal. Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis. ACR Appropriateness Criteria Table Key