[en] Small cell lung cancer (SCLC) differs from other types of lung cancer in its more aggressive clinical course and superior responsiveness to chemo- and radiotherapy. Median survival of patients with unresectable limited disease was reported only 3 months by supportive care alone. SCLC was treated by surgery in 1950s, but results were disappointing. In a British study in the 1960s, radiotherapy proved superior to surgery in survival. However, most patients treated with thoracic radiotherapy alone died of instant metastases with median survival of 5-9 months, indicating a need for primary systemic treatment. In the 1970s, combined chemotherapy came to be the main treatment for SCLC; high response rate and improved survival led to the idea that thoracic radiotherapy added only toxicities with no therapeutic advantage in chemotherapy-treated patients. Considering the fact that 80% of patients treated with chemotherapy alone relapsed in primary sites, and that radio-therapy achieved response in 90% of limited disease patients, it is reasonable to attempt to combine systemic chemotherapy and thoracic radio-therapy to improve therapeutic results for this disease. In 1980s, several randomized trials comparing chemotherapy alone versus chemotherapy with thoracic radiotherapy were conducted to clarify the role of thoracic radio-therapy in combination with chemotherapy for limited SCLC. (author). 20 refs., 3 tabs

[en] Purpose: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy. Methods and materials: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients. Results: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p < 0.001), and in 13%, 44% and 57% (p < 0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p < 0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days. Conclusion: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients

[en] The objective of this study was to identify any gender differences in the outcomes of concurrent platinum-based chemotherapy and thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). A comparative retrospective review of the clinical characteristics and treatment outcomes between female and male NSCLC patients receiving chemoradiotherapy. Of a total of 204 patients, 44 (22%) were females and 160 (78%) were males. There was no difference in age, body weight loss, performance status or disease stage between the sexes, whereas never-smokers and adenocarcinoma were more common in female patients (55% vs. 3%, P<0.001, and 73% vs. 55%, P=0.034, respectively). Full cycles of chemotherapy and radiotherapy at a total dose of 60 Gy were administered to ∼70% and >80% of the patients, respectively, of both sexes. Grade 3-4 neutropenia was observed in 64% of the female patients and 63% of the male patients. Severe esophagitis was encountered in <10% of the patients, irrespective of the sex. The response rate was higher in the female than in the male patients (93% vs. 79%, P=0.028), but the median progression-free survival did not differ between the sexes. The median survival time in the female and male patients was 22.3 and 24.3 months, respectively (P=0.64). This study failed to show any gender differences in the survival or toxicity among patients treated by concurrent chemoradiotherapy. These results contrast with the better survival in female patients undergoing surgery for localized disease or chemotherapy for metastatic disease. (author)

[en] We have conducted a multicenter phase II trial of concurrent cisplatin-etoposide (PVP) chemotherapy and radiotherapy for limited-stage small cell lung cancer (LDSCLC) to determine the effects of the concurrent administration of a PVP regimen and chest irradiation on response rate, relapse, survival and treatment toxicity. The chemotherapy regimen consisted of a four-week cycle: cisplatin (80 mg/m², given intravenously on day 1) and etoposide (100 mg/m², given intravenously on days 1-3). This cycle was given four to six times within six months. Chest irradiation to the primary tumors at both the hili and the mediastinum was administered in standard fractions on days 2-12 in the first cycle of chemotherapy and on days 29-47 in the second cycle, with a total dose of 40-50 Gy. Prophylactic cranial irradiation was performed among complete remission (CR) or good partial remission (PR) patients after completion of the concurrent therapy. A total of 66 patients were entered into the trial and 59 were evaluated. The concurrent therapy induced an overall response rate of 94.9% in 59 patients: 24 patients, 40.7% CR, 32 patients, 54.2% PR. The median response duration was 8.7 months, and the median survival time for all eligible patients was 14.8 months. The percentage of patients with two-year survival period was 20. A local relapse within the irradiated area was seen in only 22% of relapsed patients. Brain metastases occurred in 24% of patients. Four of 32 patients treated with prophylactic cranial irradiation had brain metastases. Toxic effects, chiefly grades 3 and 4 leukopenia, as established by the World Health Organization, were detected in all treated patients. Other toxicities, including radiation-induced esophagitis and pneumonitis, were deemed almost acceptable. We concluded concurrent treatment of a PVP regimen with chest irradiation to be a feasible and beneficial therapy with an efficacy compatible to that of other published reports. (J.P.N.)

[en] 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). Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly 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/m² per fraction up to the first 20 fractions. 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 Japan Clinical Oncology Group (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. 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. (author)

[en] To clarify the long-term survival data and factors that are correlated with survival outcome of unresectable locally advanced non-small cell lung cancer (NSCLC) following chemoradiotherapy, we analyzed patients who entered the Japan Clinical Oncology Group (JCOG) clinical trials for unresectable locally advanced NSCLC. Between October 1989 and August 1997, 240 patients (male 207, female 33; PS (performance status) 0 58, PS 1 172, PS 29, unknown 1; stage IIB 2, IIIA 62, IIIB 175, unknown 1) entered the 6 trials. All patients received chemotherapy and radiotherapy. The associations between survival outcome and treatment-related factors were analyzed using Cox regression analysis. Median survival times and 5-year survival rates in the trials were 11.9-19.7 months and 0-17.6%, respectively. Median survival time was 16.1 months and the 5- and 7-year survival rates of all 240 patients were 14.4% and 12.0%, respectively. No deaths were observed 7 years after initiation of the treatment or later. For stage IIIA and IIIB patients, the 5-year survival rates were 16.3% and 13.4%, respectively. Node status and age were significantly associated with survival, but no factors of the treatment were associated with survival of patients with unresectable locally advanced NSCLC. The present retrospective analysis showed that approximately 12% of patients with unresectable locally advanced NSCLC could be cured by various chemoradiotherapy regimens. (author)

[en] Purpose: To determine the maximum tolerated dose in concurrent three-dimensional conformal radiotherapy (3D-CRT) with chemotherapy for unresectable Stage III non–small-cell lung cancer (NSCLC). Patients and Methods: Eligible patients with unresectable Stage III NSCLC, age ≥20 years, performance status 0–1, percent of volume of normal lung receiving 20 GY or more (V₂₀) ≤30% received three to four cycles of cisplatin (80 mg/m² Day 1) and vinorelbine (20 mg/m² Days 1 and 8) repeated every 4 weeks. The doses of 3D-CRT were 66 Gy, 72 Gy, and 78 Gy at dose levels 1 to 3, respectively. Results: Of the 17, 16, and 24 patients assessed for eligibility, 13 (76%), 12 (75%), and 6 (25%) were enrolled at dose levels 1 to 3, respectively. The main reasons for exclusion were V₂₀ >30% (n = 10) and overdose to the esophagus (n = 8) and brachial plexus (n = 2). There were 26 men and 5 women, with a median age of 60 years (range, 41–75). The full planned dose of radiotherapy could be administered to all the patients. Grade 3–4 neutropenia and febrile neutropenia were noted in 24 (77%) and 5 (16%) of the 31 patients, respectively. Grade 4 infection, Grade 3 esophagitis, and Grade 3 pulmonary toxicity were noted in 1 patient, 2 patients, and 1 patient, respectively. The dose-limiting toxicity was noted in 17% of the patients at each dose level. The median survival and 3-year and 4-year survival rates were 41.9 months, 72.3%, and 49.2%, respectively. Conclusions: 72 Gy was the maximum dose that could be achieved in most patients, given the predetermined normal tissue constraints.

[en] Introduction: The role of elective nodal irradiation of non-small-cell lung cancer (NSCLC) patients treated with radiotherapy remains unclear. We investigated the significance of treating clinically uninvolved lymph nodes by retrospectively analyzing the relationship between loco-regional failure and the irradiated volume. Methods: Between 1998 and 2003, patients with IA-IIIB NSCLC were treated with radiotherapy. The eligibility criteria for this study were an irradiation dose of 60 Gy or more and a clinical response better than stable disease. Typical radiotherapy consisted of 40 Gy/20 fr to the tumor volumes (clinical target volume of the primary tumor [CTVp], of the metastatic lymph nodes [CTVn], and of the subclinical nodal region [CTVs]), followed by off-cord boost to CTVp+n to a total dose 60-68 Gy/30-34 fr. The relationship between the sites of recurrence and irradiated volumes was analyzed. Results: A total of 127 patients fulfilled the eligibility criteria. Their median overall and progression-free survival times were 23.5 (range, 4.2-109.7) and 9.0 months (2.2-109.7), respectively. At a median follow-up time of 50.5 months (range, 14.2-83.0) for the surviving patients, the first treatment failure was observed in 95 patients (loco-regional; 41, distant; 42, both; 12). Among the patients with loco-regional failure, in-field recurrence occurred in 38 patients, and four CTVs recurrences associated with CTVp+n failure were observed. No isolated recurrence in CTVs was observed. Conclusions: In-field loco-regional failure, as well as distant metastasis, was a major type of failure, and there was no isolated elective nodal failure. Radiation volume adequacy did not seem to affect elective nodal failure.

[en] Purpose: The purpose of this study was to refine the heterogeneous clinical stage IIIA non-small cell lung cancer (NSCLC) with N2 nodes status (cIIIA-N2) by clinicopathological characteristics before treatment. Methods and Materials: We analyzed data of consecutive patients with cIIIA-N2 NSCLC diagnosed between 1997 and 2010 and treated by chemoradiation therapy (CRT). The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the American College of Chest Physicians. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa). Results: A total of 148 patients with cIIIA-N2 NSCLC was treated by CRT. The patient characteristics were as follows: males: 118; females: 30; median age: 62 years; appearance of the involved MLNs: 85 discrete, 63 infiltrative; extent of MLNI: 82 limited, 66 extensive; histology: 36 squamous, 112 nonsquamous. The median progression-free survival (PFS) and median overall survival (OS) in the entire subject population were 9.9 and 34.7 months, respectively. A discrete appearance of the involved MLNs and a limited extent of MLNI contributed significantly to a better PFS and OS. The percentages of cases with relapses within the irradiated field classified according to the characteristics of the MLNs were as follows; appearance of the MLNs (24.6% discrete, 18.9% infiltrative); extent of MLNI (25.9 limited, 17.9% extensive). Conclusions: Those with a discrete appearance of the involved MLNs and a limited extent of MLNI at diagnosis could show relatively more favorable outcomes and could be candidates for multimodality therapy.

[en] Purpose: To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non–small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). Patients and Methods: Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. Results: A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. Conclusions: Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC