R. Komaki

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer

A retroviral vector containing the wild–type p53 gene under control of a β–actin promoter was produced to mediate transfer of wild–type p53 into human non–small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector–related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector–p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

RESPONSE, TOXICITY, FAILURE PATTERNS, AND SURVIVAL IN FIVE RADIATION THERAPY ONCOLOGY GROUP (RTOG) TRIALS OF SEQUENTIAL AND/OR CONCURRENT CHEMOTHERAPY AND RADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL-CELL CARCINOMA OF THE LUNG

PURPOSE The purpose of this study was to assess response, toxicity, failure patterns, and survival differences in three chemotherapy (ChT)/radiation therapy (RT) sequencing strategies for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Five completed Radiation Therapy Oncology Group (RTOG) trials for Stage II-IIIA/B inoperable NSCLC patients employed one of the three following strategy groupings: 1) sequential ChT followed by standard RT (60 Gy in 6 weeks); 2) combined sequential and concurrent ChT and standard RT (60 Gy in 6 weeks); or 3) concurrent ChT and hyperfractionated RT (69.6 Gy in 6 weeks). All five trials required KPS > or = 70; two trials (314 patients) required <5% weight loss and three trials (147 patients) had no minimum weight loss requirement. In all five trials the ChT used cisplatin with either vinblastine or oral etoposide. Combining data for the five trials yielded an evaluable group of 461 patients. The three methods of sequencing ChT and RT were evaluated for differences in response, acute and late toxicity, patterns of failure, and survival. Acute toxicity was defined as that occurring within 90 days from the start of RT. Late toxicity was defined as that occurring after 90 days from the start of RT. Acute or late toxicity > or = grade 3 was defined as severe. Site of first failure was recorded by date. In-field failure excluded distant metastasis as a failure and included only tissue in the RT treatment field. Overall progression-free survival (PFS) was defined as survival without evidence of intra- or extrathoracic tumor or death from any cause. RESULTS Group 1 had a lower overall response rate (63%) compared to either Group 2 (77%) or Group 3 (79%), p = 0.03 and 0.003, respectively. Overall grade 4/5 acute toxicities were nearly equal between groups. The severe nonhematologic acute toxicities were significantly different by strategy group (p < 0.0001). Group 1 and 2 were not statistically different. Group 3 had significantly more patients with severe acute nonhematologic toxicity (55%) than either Group 1 (27%) or 2 (34%) with p < 0.0001 and p = 0.0005, respectively. This was due to a severe acute esophagitis rate of 34% for Group 3 versus 1.3% for Group 1 and 6% for Group 2 (p < 0.0001 for both comparisons). Overall grade 4/5 late toxicities did not differ by group. Severe late nonhematologic toxicities were different by group (p = 0.0098). Group 1 patients had significantly fewer severe late nonhematologic toxicities (14%) compared to patients in Groups 2 (26%) or 3 (28%) (p = 0.046 and 0.038, respectively). Severe late lung toxicity was 10% for Group 1 compared to 21% and 20% for Groups 2 and 3, respectively. Severe late lung toxicities differed by group (p = 0.033), but not severe late esophagitis (p = 0.077). There were no differences between the three strategy groups for patterns of first failure. The in-field failures were higher in Group 2 (71%) compared to Groups 1 (56%) and 3 (55%), p = 0.0478. Pairwise comparisons yielded p-values of 0.068 and 0.015 for Group 2 versus 1 and Group 2 versus 3, respectively. Three-year PFS was better in Group 2 (15%) and 3 (15%) compared to Group 1 (7%), but not statistically significant (p = 0.454). Similarly, in-field PFS was better in Group 2 (17%) and 3 (20%) than Group 1 (9%), but not significant (p = 0.167). There were improvements in 3-year survival for Group 2 (17%) and Group 3 (25%) compared to Group 1 (15%), but the differences were not statistically significant (p = 0.47). The same results were present for patients with less than 5% weight loss and patients with stage IIIA tumors. CONCLUSION Thus, concurrent ChT and hyperfractionated RT had a higher incidence of severe acute esophageal toxicity. Severe late lung toxicity with concurrent ChT/hyperfractionated RT, as well as with induction ChT followed by concurrent ChT/standard RT, may be greater compared to sequential ChT/RT. (ABSTRACT TRUNCATED)

CONSIDERATION OF DOSE LIMITS FOR ORGANS AT RISK OF THORACIC RADIOTHERAPY: ATLAS FOR LUNG, PROXIMAL BRONCHIAL TREE, ESOPHAGUS, SPINAL CORD, RIBS, AND BRACHIAL PLEXUS

PURPOSE To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. METHODS AND MATERIALS The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy and 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists. RESULTS Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed. CONCLUSIONS We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.

Radiotherapy Patterns of Care Study in Lung Carcinoma

Purpose: For the first time, a lung Patterns of Care Study was conducted to determine the national patterns of radiation (RT) practice in patients treated for nonmetastatic lung cancer in 1998 to 1999. Materials and Methods: A national survey of randomly selected RT institutions in the United States was conducted using two-stage cluster sampling, stratified by practice type. Patients with nonmetastatic lung cancer (Karnofsky performance score [KPS] ≥ 60), who received RT as definitive or adjuvant therapy, were randomly selected. To determine national estimates, sample size was weighted by the relative number of institutions per strata and the number of patient records reviewed per the number of patients eligible. Accordingly, 42,335 patient records from 58 institutions were reviewed by trained research associates. The unweighted sample size (or number of patients) was 541. Results: The histologies were small-cell lung cancer (SCLC) in 14.5% of patients versus non–small-cell lung cancer (NSCLC) in 85.5% of...

Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

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

PURPOSE The standard treatment for patients with locally advanced inoperable non-small-cell lung cancer and good prognostic factors has become combined chemotherapy (ChT) and radiotherapy (RT). However, the sequencing of the two modalities, as well as fractionation of RT, has been controversial. The Radiation Therapy Oncology Group (RTOG) Study 92-04 was a randomized Phase II study designed to evaluate further the toxicity and efficacy of 2 different strategies of chemoradiation evaluated in 2 prior RTOG Phase II studies. METHODS Patients with Stage II or III medically inoperable or unresectable non-small-cell lung cancer, good performance status, and minimal weight loss were enrolled into a prospective randomized Phase II RTOG study. Arm 1 consisted of induction ChT (vinblastine 5 mg/m(2) i.v. bolus weekly for the first 5 weeks, and cisplatin, 100 mg/m(2) i.v. on Days 1 and 29) followed by concurrent ChT/RT (cisplatin 75 mg/m(2) i.v. on Days 50, 71, and 92) during thoracic radiotherapy (63 Gy in 34 fractions during 7 weeks starting on Day 50). Arm 2 was concurrent ChT and hyperfractionated RT starting on Day 1 with a total dose of 69.6 Gy in 58 fractions during 6 weeks, 1.2 Gy/fraction b.i.d. ChT consisted of cisplatin, 50 mg/m(2) i.v. on Days 1 and 8, and oral VP-16, 50 mg b.i.d. for 10 days only on the days of thoracic radiotherapy repeated on Day 29. RESULTS A total of 168 patients were entered between 1992 and 1994, and 163 patients were eligible for analysis. Eighty-one patients were treated in Arm 1 and 82 patients in Arm 2. Pretreatment characteristics, including age, gender, Karnofsky performance status, histologic features, and stage, were similar. The incidence of acute esophagitis was significantly higher among patients treated in Arm 2 than among those treated in Arm 1 (p <0.0001). The incidence of acute hematologic toxicity was significantly higher among patients treated in Arm 1 (p = 0.01 for anemia and p = 0.03 for other hematologic toxicities) than among those treated in 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. CONCLUSION Concurrent ChT and hyperfractionated RT resulted in a significant prolongation of the time to in-field progression, but with higher acute and chronic esophagitis. No other significant differences were observed between the two groups. Investigation with a chemoradio-protector is under way.

Carcinoma of the cervix: Patterns of care studies: Review of 1978, 1983, and 1988–1989 surveys

PURPOSE A review of the Patterns of Care Studies Process Survey data on carcinoma of the cervix conducted on patients in 1978, 1983, and 1988-89 was carried out to identify changes or trends in the demographics, evaluation, and treatment that might have occurred over this time period. METHODS AND MATERIALS Patterns of Care Studies conducted surveys on patients treated by radiation therapy for cervical carcinoma in 1978, 1983, and 1988-89. These surveys have compiled demographic and treatment data on a total of 993 patients. There is outcome data for the 1978 and 1983 surveys, but not for the 1988-89 survey because follow-up has not been collected yet. The demographic and treatment delivery data on all three surveys has been reviewed and analyzed and is the subject of this study. RESULTS There was no difference in the age distribution at the time of diagnosis of the patients in these surveys. The percentage of black patients remained constant in the three surveys, 19%, 17%, and 21%, respectively. The percentage of white patients was 76%, 78%, and 67%, but that of nonwhite/nonblack patients was 3%, 4%, and 12% (p < 0.001). The distribution of patients by stage was similar in the first two surveys. In the third survey, there was a decrease in the percentage of patients with Stage IA and IB (first = 35%; second = 38%; third = 29%) with a concurrent increase in Stage IIIA and IIIB patients (first = 20%; second = 18%; third = 26%). The surveys showed a major change in the pretreatment evaluation tests used. There was a progressive decrease in the use of intravenous pyelogram (IVP) (86 to 42%), barium enema (58 to 32%), cystoscopy for patients Stage IIB and higher (64 to 52%), and lymphangiography (18 to 14%). The use of abdominal or pelvic computed tomography dramatically increased from 6 to 70% between the first and third surveys. The use of 60Co units decreased from 35 to 2% from the first to the third survey [6 to 0% for short source-surface distance (SSD) 60Co units]. Point dose calculations for the intracavitary therapy increased from 78% in the 1978 survey to 95% in the third survey. As determined by the total dose delivered to the paracentral points, more patients (75.1%) were treated according to the Patterns of Care recommended guidelines in the 1988-89 survey than in the 1983 survey (63.6%). Chemotherapy was given to 12% of the patients undergoing radiation therapy during the period of the third survey, but these data are not available for the first and second surveys. CONCLUSION Review of the Carcinoma of the Cervix Patterns of Care studies discloses significant changes in the demographics, patient evaluation, and radiation therapy techniques during the period of the studies. The potential impact of these changes on treatment outcome cannot be determined at this time until longterm follow-up for the 1988-89 survey is available, but improvements in the processes of care should lead to improvements in outcome.

A PHASE II STUDY OF A PACLITAXEL-BASED CHEMORADIATION REGIMEN WITH SELECTIVE SURGICAL SALVAGE FOR RESECTABLE LOCOREGIONALLY ADVANCED ESOPHAGEAL CANCER: INITIAL REPORTING OF RTOG 0246

PURPOSE The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. METHODS AND MATERIALS The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (α = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg(2)/day), cisplatin (15 mg/mg(2)/day), and paclitaxel (200 mg/mg(2)/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg(2)/day) with cisplatin (15 mg/mg(2)/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. RESULTS Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was ≥T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. CONCLUSIONS In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%-82%).

ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients

Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase‐1 (ALDH‐1) could be associated with response.

Modulation of c-Met signaling and cellular sensitivity to radiation: potential implications for therapy.

The c‐Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial‐mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c‐Met has also been observed after irradiation, suggesting that c‐Met participates in radiation‐induced disease progression through the epithelial‐mesenchymal transition. Therefore, c‐Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c‐Met and discusses studies performed to date in which c‐Met inhibition was used as a strategy to increase cellular radiosensitivity. Cancer 2013.