The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Treatment of stage II non-small cell lung cancer. Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812). Predictors of grade ≥ 2 and grade ≥ 3 radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal radiotherapy Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. The value of combined‐modality therapy in elderly patients with stage III nonsmall cell lung cancer Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. Long‐term observations of the patterns of failure in patients with unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy report by the radiation therapy oncology group
Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Based on clinical assessment alone , patients with stage II non-small cell lung cancer ( NSCLC ) comprise only 5 % of all patients with NSCLC . In addition , patients with stage II NSCLC represent a heterogeneous group , since stage II consists of patients with T1 - 2N1 or T3N0 tumors . By definition , patients with tumor invading the chest wall apex , mediastinum , diaphragm , or even the mainstem bronchus may all have T3 tumors . The extent of the data available regarding treatment of each of these different groups is therefore limited . The quality of the data is limited as well , because information often comes from small series of patients . Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization , since data from large , r and omized studies of adjuvant radiation therapy , chemotherapy , or a combination of the two are available for analysis . Superior sulcus tumors are discussed elsewhere in these guidelines BACKGROUND The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer ( NSCLC ) . METHODS Eligible patients were 71 years of age or older with unresectable stage III NSCLC . Patients were r and omly assigned to the radiotherapy alone ( RT ) arm , irradiation with 60 Gy ; or the chemoradiotherapy ( CRT ) arm , the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2 ) per fraction up to the first 20 fractions . RESULTS This study was terminated early when 46 patients were registered from November 1999 to February 2001 . Four patients ( one in the RT arm , three in the CRT arm ) were considered to have died due to treatment-related causes . The JCOG Radiotherapy Committee assessed these treatment-related deaths ( TRDs ) and the compliance with radiotherapy in this trial . They found that 60 % of the cases corresponded to protocol deviation and 7 % were protocol violation in dose constraint to the normal lung , two of whom died due to radiation pneumonitis . As to the effectiveness for the 46 patients enrolled , the median survival time was 428 days [ 95 % confidence interval ( CI ) = 212 - 680 days ] in the RT arm versus 554 days ( 95 % CI = 331 to not estimable ) in the CRT arm . CONCLUSIONS Due to the early termination of this study , the effectiveness of concurrent use of carboplatin remains unclear . We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee Abstract Grade ≥ 3 radiation pneumonitis ( RP ) is generally severe and life-threatening . Predictors of grade ≥ 2 are usually used for grade ≥ 3 RP prediction , but it is unclear whether these predictors are appropriate . In this study , predictors of grade ≥ 2 and grade ≥ 3 RP were investigated separately . The increased risk of severe RP in elderly patients compared with younger patients was also evaluated . Material and methods . A total of 176 consecutive patients with locally advanced non-small cell lung cancer were followed up prospect ively after three-dimensional conformal radiotherapy . RP was grade d according to Common Terminology Criteria for Adverse Events version 3.0 . Results . Mean lung dose ( MLD ) , mean heart dose , ratio of planning target volume to total lung volume ( PTV/Lung ) , and dose-volume histogram comprehensive value of both heart and lung were associated with both grade ≥ 2 and grade ≥ 3 RP in univariate analysis . In multivariate logistic regression analysis , age and MLD were predictors of both grade ≥ 2 RP and grade ≥ 3 RP ; receipt of chemotherapy predicted grade ≥ 3 RP only ; and sex and PTV/Lung predicted grade ≥ 2 RP only . Among patients who developed high- grade RP , MLD and PTV/Lung were significantly lower in patients aged ≥ 70 years than in younger patients ( p < 0.05 for both comparisons ) . Conclusions . The predictors were not completely consistent between grade ≥ 2 RP and grade ≥ 3 RP . Elderly patients had a higher risk of severe RP than younger patients did , possibly due to lower tolerance of radiation to the lung PURPOSE Here we report the results of a phase III study , to evaluate whether the addition of cisplatin to radiation therapy ( XRT ) would improve progression-free survival or overall survival for patients with locally advanced unresectable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Two hundred forty patients with biopsy-proven unresectable NSCLC without distant metastases or lower-stage medically inoperable patients were r and omized to one of two treatment arms . Arm A consisted of thoracic XRT alone , 60 to 65 Gy total tumor dose in daily fractions of 1.80 to 2.00 Gy ; and arm B consisted of identical XRT with the addition of cisplatin 70 mg/m2 every 3 weeks for three cycles beginning on the first day of irradiation . RESULTS Two hundred fifteen patients were eligible and assessable . The overall response rate was 50 % on the combination arm versus 38 % on the XRT-alone arm ( P = .076 ) . The median progression-free survival time was 23 versus 22 weeks , respectively ( P = .0537 ) . The median survival time was 43 weeks on the combination arm versus 46 weeks on the XRT arm ( Poverall = .3469 ) . The 1- , 2- , and 5-year survival rates were 43 % , 18 % , and 5 % on the combination arm versus 45 % 13 % , and 2 % on the XRT arm , respectively . CONCLUSION Cisplatin , administered every 3 weeks , does not significantly improve response rate , progression-free survival , or overall survival when added to thoracic XRT for locally advanced unresectable NSCLC BACKGROUND High-dose radiation therapy is generally recommended as st and ard treatment in regionally advanced unresectable non-small-cell lung cancer ( NSCLC ) , but median- and long-term survival remain poor . Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens . Therefore , we design ed a r and omized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone . PATIENTS AND METHODS From March , 1984 to December , 1988 , 66 consecutive patients with stage III unresectable NSCLC were r and omized to one of two treatment arms ; 61 were evaluable for survival and 58 for response and toxicity . Patients r and omly assigned to arm A received cisplatin ( CDDP 100 mg/m2 on day 1 ) and etoposide ( VP 16 120 mg/m2 on days 1 , 2 , 3 ) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes . Patients assigned to arm B received only the same radiotherapy . The 61 eligible patients were comparable in terms of age , performance status , histology and treatment . RESULTS Response rate was 53 % in arm A and 32 % in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm . At six years of follow-up all the patients were dead . Toxicity was mild and no treatment-related deaths were recorded . CONCLUSION Induction chemotherapy produced a better response rate and a trend of improved survival ( 4 months ) but a significant survival advantage was not achieved ( p < 0.11 ) , probably because of the small number of patients enrolled in the trial PURPOSE Older adults are vulnerable to chemotherapy toxicity ; however , there are limited data to identify those at risk . The goals of this study are to identify risk factors for chemotherapy toxicity in older adults and develop a risk stratification schema for chemotherapy toxicity . PATIENTS AND METHODS Patients age ≥ 65 years with cancer from seven institutions completed a prechemotherapy assessment  that captured sociodemographics , tumor/treatment variables , laboratory test results , and geriatric assessment variables ( function , comorbidity , cognition , psychological state , social activity/support , and nutritional status ) . Patients were followed through the chemotherapy course to capture grade 3 ( severe ) , grade 4 ( life-threatening or disabling ) , and grade 5 ( death ) as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events . RESULTS In total , 500 patients with a mean age of 73 years ( range , 65 to 91 years ) with stage I to IV lung ( 29 % ) , GI ( 27 % ) , gynecologic ( 17 % ) , breast ( 11 % ) , genitourinary ( 10 % ) , or other ( 6 % ) cancer joined this prospect i ve study . Grade 3 to 5 toxicity occurred in 53 % of the patients ( 39 % grade 3 , 12 % grade 4 , 2 % grade 5 ) . A predictive model for grade 3 to 5 toxicity was developed that consisted of geriatric assessment variables , laboratory test values , and patient , tumor , and treatment characteristics . A scoring system in which the median risk score was 7 ( range , 0 to 19 ) and risk stratification schema ( risk score : percent incidence of grade 3 to 5 toxicity ) identified older adults at low ( 0 to 5 points ; 30 % ) , intermediate ( 6 to 9 points ; 52 % ) , or high risk ( 10 to 19 points ; 83 % ) of chemotherapy toxicity ( P < .001 ) . CONCLUSION A risk stratification schema can establish the risk of chemotherapy toxicity in older adults . Geriatric assessment variables independently predicted the risk of toxicity PURPOSE The North Central Cancer Treatment Group performed a phase III trial to determine whether chemotherapy plus either bid radiation therapy ( RT ) or daily ( qd ) RT result ed in a better outcome for patients with stage III non-small-cell lung cancer ( NSCLC ) . No difference in survival was identified between the two arms . This secondary analysis was performed to examine the relationship between patient age and outcome . PATIENTS AND METHODS Two hundred forty-six patients were r and omized to receive etoposide plus cisplatin and either RT qd or split-course RT bid . This retrospective study compared the outcomes of patients aged > /=70 years ( " elderly patients ") with those of younger individuals . Of the 244 assessable patients , 63 ( 26 % ) were elderly , and 181 ( 74 % ) were younger individuals . RESULTS The 2-year and 5-year survival rates were 39 % and 18 % , respectively , in patients younger than 70 years , compared with 36 % and 13 % , respectively , in elderly patients ( P = .4 ) . Grade 4 + toxicity occurred in 62 % of patients younger than 70 years compared with 81 % of elderly patients ( P = .007 ) . Grade 4 + hematologic toxicity occurred in 56 % of patients younger than 70 years , compared with 78 % of elderly patients ( P = .003 ) . Grade 4 + pneumonitis occurred in 1 % of those younger than 70 years , compared with 6 % of elderly patients ( P = .02 ) . CONCLUSION Toxicity , especially myelosuppression and pneumonitis , was more pronounced in the elderly patients receiving combined-modality therapy for locally advanced NSCLC . Despite increased toxicity , elderly patients have survival rates equivalent to younger individuals . Therefore , fit , elderly patients with locally advanced NSCLC should be encouraged to receive combined-modality therapy , preferably on clinical trials with cautious , judicious monitoring . Future studies should explore ways to decrease toxicity of therapy in elderly patients The objective of this study was to assess the value of combined‐modality therapy in elderly patients by comparing the differences in outcome between patients who received radiotherapy ( RT ) alone  and patients who received  RT plus chemotherapy  for stage III nonsmall cell lung cancer ( NSCLC ) BACKGROUND For many years , high dose radiation therapy was the st and ard treatment for patients with locally or regionally advanced non-small-cell lung cancer ( NSCLC ) , despite a 5-year survival rate of only 3%-10 % following such therapy . From May 1984 through May 1987 , the Cancer and Leukemia Group B ( CALGB ) conducted a r and omized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up . PURPOSE This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial . METHODS The patient population consisted of individuals who had clinical or surgical stage III , histologically documented NSCLC ; a CALGB performance status of 0 - 1 ; less than 5 % loss of body weight in the 3 months preceding diagnosis ; and radiographically visible disease . Patients were r and omly assigned to receive either 1 ) cisplatin ( 100 mg/m2 body surface area intravenously on days 1 and 29 ) and vinblastine ( 5 mg/m2 body surface area intravenously weekly on days 1 , 8 , 15 , 22 , and 29 ) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 ( CT-RT group ) or 2 ) radiation therapy with 6000 cGy alone beginning on day 1 ( RT group ) for a maximum duration of 6 - 7 weeks . Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects , disease progression , and date of death . RESULTS There were 78 eligible patients r and omly assigned to the CT-RT group and 77 r and omly assigned to the RT group . Both groups were similar in terms of sex , age , histologic cell type , performance status , substage of disease , and whether staging had been clinical or surgical . All patients had measurable or evaluable disease at the time of r and om assignment to treatment groups . Both groups received a similar quantity and quality of radiation therapy . As previously reported , the rate of tumor response , as determined radiographically , was 56 % for the CT-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 CT-RT group ( 13.7 months ) than for the RT group ( 9.6 months ) ( P = .012 ) as ascertained by the logrank test ( two-sided ) . The percentages of patients surviving after years 1 through 7 were 54 , 26 , 24 , 19 , 17 , 13 , and 13 for the CT-RT group and 40 , 13 , 10 , 7 , 6 , 6 , and 6 for the RT group . CONCLUSIONS Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival . The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone . However , inasmuch as 80%-85 % of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone , the need for further improvements in both the local and systemic treatment of this disease persists This report details the patterns of tumor recurrence in two prospect i ve r and omized studies involving 551 patients with histologically proven unresectable or medically inoperable non‐oat cell carcinoma of the lung treated with definitive radiotherapy .  Patients were treated according to two protocol s , depending on the stage of the tumor : ( 1 ) Patients with T1 , 2 , 3‐NO , 1 , 2 tumors were r and omized to four different regimens : 4000 cGy split course ( 2000 cGy in five fractions , per 1 week , 2 weeks rest and additional 2000 cGy in five fractions , per 1 week ) or 4000 , 5000 , or 6000 cGy continuous courses , five fractions per week . ( 2 ) Patients with T4 , any N or N3 , any T stage tumors were r and omized to be treated with 3000 cGy tumor dose ( TD ) , ten fractions in 2 weeks , 4000 cGy split course ( described above ) , or 4000 cGy continuous course . In the patients with less advanced tumors ( Study 1 ) the intrathoracic failure rate within the irradiated volume was 48 % with 4000 cGy continuous , 38 % with 4000 cGy split course or 5000 cGy continuous , and 27 % for patients receiving 6000 cGy continuous course . The failure rate in the nonirradiated lung ranged from 25 % to 30 % in the various groups . Patients with adenocarcinoma or large cell undifferentiated carcinoma had better intrathoracic tumor control ( 35 % ) than those with squamous cell carcinoma ( 20 % ) . The incidence of distant metastases was 75 % to 80 % in all histologic groups . Distant metastases appeared sooner after therapy in the patients with adenocarcinoma or large cell undifferentiated carcinoma . The initial failure rate in the brain was 7 % in patients with squamous cell carcinoma , 19 % with adenocarcinoma , and 13 % in patients with large cell carcinoma .  The ultimate incidence of brain metastases was 16 % in squamous cell carcinoma , and 30 % for adenocarcinoma or large cell undifferentiated carcinoma . Higher doses of irradiation will be necessary in order to improve the intrathoracic tumor control . Clinical trials by the Radiation Therapy Oncology Group , some of them involving multiple daily fractionation , are in progress . Furthermore , because of the high incidence of distant metastases , effective systemic cytotoxic agents are critically needed to improve survival of lung cancer patients . The high frequency of brain metastases suggests that , as in small cell carcinoma of the lung , elective irradiation of the brain may be necessary , if not to improve survival to enhance the quality of life of patients with adenocarcinoma and large cell carcinoma
In stage III non-small cell lung cancer ( NSCLC ) , the st and ard of care in young patients is chemoradiotherapy , but this st and ard is not as clearly established for older patients .
We aim ed to determine the efficacy and harm associated with chemoradiotherapy versus radiotherapy alone in elderly ( ≥70 years ) , stage III NSCLC patients through a systematic review .