Definitive carbon ion radiotherapy for tracheobronchial adenoid cystic carcinoma: a preliminary report.

BACKGROUND: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC. METHODS: The inclusion criteria were as follows: 1) age 18-80 years; 2) Eastern Cooperative Oncology Group Performance Status 0-2; 3) histologically confirmed TACC; 4) stage III-IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66-72.6 GyE/22-23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Eighteen patients with a median age of 48 (range 30-73) years were enrolled. The median follow-up time was 20.7 (range 5.8-44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2-41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed. CONCLUSIONS: CIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.

Stage IVb thymic carcinoma: patients with lymph node metastases have better prognoses than those with hematogenous metastases.

BACKGROUND: This study aimed to analyze the pattern of lymphogenous and hematogenous metastases in patients with stage IVb thymic carcinomas and identify prognostic factors for their survivals. METHODS: Between September 1978 and October 2014, 68 patients with pathologically confirmed stage IVb thymic carcinomas were treated at Fudan University Shanghai Cancer Center. Forty-three patients had lymph node involvement without distant metastases, and the remaining 25 patients had hematogenous metastases. Clinical-pathological characteristics, including age, sex, histologic subtype, tumor size, metastasis, treatment modalities, such as surgical resection, radiotherapy, and chemotherapy, and clinical outcomes, such as overall survival (OS) and progression free survival (PFS), were analyzed. RESULTS: The median follow-up time was 22 months (range, 1-126 months). The median OS of all patients with stage IVb thymic carcinomas was 30 months, and the 5-year overall survival rate was 25.1%. The median PFS was 11 months, and the 5-year PFS was 17.9%. Stage IVb patients with lymph node involvement had a better survival than those with distant metastasis (40 vs. 20 months, p = 0.002). Patients with myasthenia gravis had a worse prognosis (p = 0.033). Multivariate analysis identified metastatic status as an independent prognostic factor for OS in patients with stage IVb thymic carcinomas. CONCLUSIONS: Patients with lymph node involvement had a better survival than those with distant metastases. Much work remains to investigate the prognosis of patients with stage IVb thymic carcinomas and to explore different treatment strategies for patients with lymph node involvement and distant metastases.

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study.

PURPOSE: The safety and efficacy of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for patients with esophageal squamous cell carcinoma were evaluated in a single-institution phase II setting. METHODS AND MATERIALS: Between June 2007 and October 2009, 45 patients underwent concurrent chemoradiotherapy (n = 27) or radiotherapy alone (n = 18). Two planning target volumes (PTV) were defined for the SIB: PTVC and PTVG, with prescribed doses of 50.4 Gy to the PTVC (1.8 Gy/fraction) and 63 Gy to the PTVG (2.25 Gy/fraction), both given in 28 fractions. RESULTS: At a median follow-up interval of 20.3 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 42.2 and 40.7 %, respectively. The median overall survival time was 21 months; locoregional control rates were 83.3 % at 1 year and 67.5 % at 3 years. According to CTCAE (version 3.0) criteria, none of the patients developed grade 4-5 toxicity. The most common grade 2 and 3 radiation-related toxicity was radiation esophagitis, occurring in 64 % of all patients (but only 13 % as grade 3). No patient developed grade > 2 pulmonary complications. CONCLUSION: SIB-IMRT is a feasible therapeutic approach for esophageal carcinoma patients and provides encouraging locoregional control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies.

Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis.

BACKGROUND: Concurrent chemoradiotherapy has been standard of care for unresectable esophageal carcinoma. There were no reports on proton radiotherapy (PRT) plus carbon-ion radiotherapy (CIRT) with pencil beam scanning (PBS) for esophageal carcinoma. This study evaluated the tolerability and efficiency of proton and sequential carbon-ion boost radiotherapy for esophageal carcinoma. METHODS: From April 2017 to July 2020, 20 patients with primary esophageal carcinoma at stages II-IV were treated with PRT plus sequential CIRT with PBS. A median relative biological effectiveness-weighted PRT dose of 50 Gy in 25 fractions, and a sequential CIRT dose of 21 Gy in 7 fractions were delivered. Respiratory motion management was used if the tumor moved > 5 mm during the breathing cycle. A dosimetric comparison of photon intensity-modulated radiotherapy (IMRT), PRT, and CIRT was performed. The median times and rates of survivals were estimated using the Kaplan-Meier method. Comparison of the dose-volume parameters of the organs at risk employed the Wilcoxon matched-pairs test. RESULTS: Twenty patients (15 men and 5 women, median age 70 years) were included in the analysis. With a median follow-up period of 25.0 months, the 2-year overall survival and progression-free survival rates were 69.2% and 57.4%, respectively. The patients tolerated radiotherapy and chemotherapy well. Grades 1, 2, 3, and 4 acute hematological toxicities were detected in 25%, 30%, 10%, and 30% of patients, respectively. Grades 3-5 acute non-hematological toxicities were not observed. Late toxicity events included grades 1, 2, and 3 in 50%, 20%, and 10% (pulmonary and esophageal toxicity in each) of patients. Grades 4-5 late toxicities were not noted. PRT or CIRT produced lower doses to organs at risk than did photon IMRT, especially the maximum dose delivered to the spinal cord and the mean doses delivered to the lungs and heart. CONCLUSIONS: PRT plus CIRT with PBS appears to be a safe and effective treatment for esophageal carcinoma. PRT and CIRT delivered lower doses to organs at risk than did photon IMRT. Further investigation is warranted.

New prognostic system specific for epidermal growth factor receptor-mutated lung cancer brain metastasis.

Introduction: Brain metastases (BM) from lung cancer are heterogeneous, and accurate prognosis is required for effective treatment strategies. This study aimed to identify prognostic factors and develop a prognostic system exclusively for epidermal growth factor receptor (EGFR)-mutated lung cancer BM. Methods: In total, 173 patients with EGFR-mutated lung cancer from two hospitals who developed BM and received tyrosine kinase inhibitor (TKI) and brain radiation therapy (RT) were included. Univariate and multivariate analyses were performed to identify significant EGFR-mutated BM prognostic factors to construct a new EGFR recursive partitioning analysis (RPA) prognostic index. The predictive discrimination of five prognostic scoring systems including RPA, diagnosis-specific prognostic factors indexes (DS-GPA), basic score for brain metastases (BS-BM), lung cancer using molecular markers (lung-mol GPA) and EGFR-RPA were analyzed using log-rank test, concordance index (C-index), and receiver operating characteristic curve (ROC). The potential predictive factors in the multivariable analysis to construct a prognostic index included Karnofsky performance status, BM at initial lung cancer diagnosis, BM progression after TKI, EGFR mutation type, uncontrolled primary tumors, and number of BM. Results and discussion: In the log-rank test, indices of RPA, DS-GPA, lung-mol GPA, BS-BM, and EGFR-RPA were all significant predictors of overall survival (OS) (p ≤ 0.05). The C-indices of each prognostic score were 0.603, 0.569, 0.613, 0.595, and 0.671, respectively; The area under the curve (AUC) values predicting 1-year OS were 0.565 (p=0.215), 0.572 (p=0.174), 0.641 (p=0.007), 0.585 (p=0.106), and 0.781 (p=0.000), respectively. Furthermore, EGFR-RPA performed better in terms of calibration than other prognostic indices.BM progression after TKI and EGFR mutation type were specific prognostic factors for EGFR-mutated lung cancer BM. EGFR-RPA was more precise than other models, and useful for personal treatment.

Preliminary Safety and Efficacy of Proton Plus Carbon-Ion Radiotherapy With Concurrent Chemotherapy in Limited-Stage Small Cell Lung Cancer.

OBJECTIVES: This study aimed to investigate the tolerance and effect of proton plus carbon-ion radiotherapy with concurrent chemotherapy in limited-stage small cell lung cancer using the pencil beam scanning technique. MATERIALS AND METHODS: From March 2017 to April 2020, 25 patients with limited-stage small cell lung cancer treated with combined proton and carbon-ion radiotherapy were analyzed. The primary lesions and involved lymph nodes were irradiated using 2-4 portals. Proton and sequential carbon-ion beams were delivered with a median dose of 67.1 (range, 63-74.8) GyE as fraction doses of 2.0-2.2 GyE with proton beams in 20-23 fractions and 3.0-3.8 GyE with carbon ions in 5-8 fractions. Chemotherapy was delivered concurrently with radiotherapy in all patients. RESULTS: At the last follow-up, the 2-year overall and locoregional progression-free survival rates were 81.7% and 66.7%, respectively. Radiochemotherapy was well tolerated, with grade 1, 2, and 3 acute toxicities occurring in 12.0%, 68.0%, and 20.0% of patients, respectively. All grade 3 acute toxicities were hematologically related changes. One patient experienced grade 3 acute non-hematological toxicity in the esophagus, and one other patient had grade 3 bronchial obstruction accompanied by obstructive atelectasis as a late side effect. CONCLUSION: Proton plus carbon-ion radiotherapy using pencil beam scanning yielded promising survival rates and tolerability in patients with limited-stage small cell lung cancer. A prospective clinical study is warranted to validate the therapeutic efficacy of particle radiotherapy in combination with chemotherapy in limited-stage small cell lung cancer.

Sequential boost of intensity-modulated radiotherapy with chemotherapy for inoperable esophageal squamous cell carcinoma: A prospective phase II study.

PURPOSE: This prospective phase II study aimed to determine the efficacy and tolerability of sequential boost of intensity-modulated radiation therapy (IMRT) with chemotherapy for patients with inoperable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with histologically or cytologically proven inoperable ESCC were enrolled in this study (ChiCTR-OIC-17010485). A larger target volume for subclinical lesion was irradiated with 50 Gy, and then, a smaller target volume only including gross tumor was boosted to 66 Gy. The fraction dose was 2 Gy, and no elective node was irradiated. Concurrent and consolidation chemotherapy of fluorouracil (600 mg/m2 , days 1-3) plus cisplatin (25 mg/m2 , days 1-3) was administered every 4 weeks, for 4 cycles in total. The primary endpoint was 2-year progression-free survival (PFS). RESULTS: Eighty-eight patients were enrolled in this study. The median age was 65 years (range: 45-75 years), and 69 patients (78.4%) were men. With the median follow-up of 26 (range: 3-95) months, the 2- and 5-year PFS were 39.3% and 36.9%, respectively, and overall survival (OS) were 57.1% and 39.2%, respectively. Tumor stage and concurrent chemotherapy were independent OS predictors. Major acute adverse events were myelosuppression and esophagitis, most of which were grades 1-2. Nine percent and 2.3% of patients had grade 3 acute esophagitis and late esophageal strictures, respectively. CONCLUSIONS: Sequential boost to 66 Gy by IMRT with chemotherapy was safe and effective for inoperable ESCC. A randomized phase III study to compare with standard dose of 50 Gy is warranted.

Intensity Modulated Radiation Therapy Plus Etoposide/Cisplatin for Patients With Limited Advanced Unresectable Thymic Epithelial Tumors: A Prospective Phase 2 Study.

PURPOSE: This prospective phase 2 study evaluated the efficacy and safety of intensity modulated radiation therapy plus etoposide/cisplatin (EP) for patients with unresectable thymic epithelial tumors (TETs). METHODS AND MATERIALS: Patients with limited advanced unresectable TETs whose lesions could be encompassed within radiation fields were enrolled in this study. Two cycles of EP (75 mg/m2 etoposide and 25 mg/m2 cisplatin on days 1-3 and days 29-31) were administered concurrently with radiation therapy, followed by 2 cycles after radiation therapy. The primary endpoint was the objective response rate. The secondary endpoints were the progression-free survival rate, overall survival rate, and incidence of adverse events. RESULTS: Fifty-six patients were enrolled between June 2011 and May 2018. Twenty-two and 34 patients had thymomas and thymic carcinomas, respectively. The median age was 52 (range, 21-76) years, and 30 patients (53.6%) were men. Eight patients (14.3%) had stage III tumors, 6 (10.7%) had stage IVA tumors, and 42 (75.0%) had stage IVB tumors. The objective response rate was 85.7% (95% confidence interval, 76.3%-95.2%). With a median follow-up of 46 (range, 7-101) months, the 1-, 2-, and 5-year progression-free survival rates were 66.1%, 48.0%, and 29.5%, and the 1-, 2-, and 5-year overall survival rates were 91.0%, 76.2%, and 56.2%, respectively. The most common grade 3 to 4 adverse event was leukopenia (42.9%). Pulmonary fibrosis was also observed (5.3%). CONCLUSIONS: Because intensity modulated radiation therapy with EP is effective and safe for limited advanced unresectable TETs, it could be a suitable treatment option for such patients.

Prognostic predictors and long-term outcome of postoperative irradiation in thymoma: a study of 241 patients.

The purpose of this study was to identify the prognostic predictors treated with postoperative irradiation in patients with thymoma. Two hundred forty-one patients with histologically confirmed thymoma were collected and retrospectively reviewed in this study. Fifty-four patients had stage I disease; 57, stage II; 120, stage III; 10, stage IV. One hundred sixty patients underwent total thymectomy; 63, partial resection; 18, debulking or biopsy. Patients were irradiated after surgery with median dose of 50 Gy by conventional fractionation. The overall survival rates at 5 and 10 years were 83.1% and 72.6%, respectively. The 10-year overall survival was 87% for stage I, 78.7% for stage II, 57.4% for stage III, and 24.3% for stage IV. The conclusions were drawn from this analysis. For stage I, the role of postoperative irradiation needed further investigation. For stage II-III, surgery and postoperative irradiation should be part of standard care. The favorable prognostic predictors were female, early stage, and surgical extirpation.

Three-dimensional conformal radiation therapy alone for esophageal squamous cell carcinoma: 10-year survival outcomes.

BACKGROUND: Concurrent chemoradiation is the standard treatment for locally advanced esophageal squamous cell carcinoma (SCC). We conducted a phase II study to explore the effect of three-dimensional conformal radiotherapy (3-DCRT) alone for patients with locally advanced esophageal SCC. This study aimed to analyze the long-term survival outcomes. METHODS: Between November 2004 and April 2007, 30 patients with thoracic esophageal SCC underwent late-course sequential boost 3-DCRT at Fudan University Shanghai Cancer Center. The planning target volume (PTV1) comprised a 1.2-1.5 cm lateral margin around the gross tumor volume and a 3.0 cm margin, superior and inferior to the gross tumor volume. PTV2 encompassed the gross tumor volume with a margin of 0.5-0.7 cm. The PTV1 dose delivered was 50 Gy, and the PTV2 dose was a boost dose of 16 Gy, resulting in a total dose of 66 Gy. No chemotherapy was administered. RESULTS: The median follow-up time was 30 months for all patients, and 132 months for patients who were alive. The median overall survival was 27 months (95% confidence interval [CI] 18.9-35.0). The 2-, 5-, and 10-year overall survival rates were 56.6%, 33.3%, and 26.6%, respectively. The median progression-free survival was 14 months (95% CI 7.7-20.2 months), and the 2-, 5-, and 10-year progression-free survival rates were 33.3%, 30.0%, and 26.6%, respectively. No severe late toxicity was observed in long-term survivors. CONCLUSION: Late-course sequential boost 3-DCRT is safe and feasible with promising long-term outcomes for esophageal SCC.

Simultaneously avoiding the hippocampus and hypothalamic-pituitary axis during whole brain radiotherapy: A planning study.

Whole brain radiotherapy (WBRT) is the preferred treatment for multiple brain metastases, and patients with limited-stage small cell lung cancer undergo prophylactic cranial irradiation after complete remission. However, neurotoxicity remains a complication. In addition to protecting the hippocampus from irradiation to preserve cognitive function, it is also critical to avoid irradiating the hypothalamic-pituitary axis to preserve endocrine and immune function. This study aimed to evaluate the feasibility of delivering WBRT while protecting the hippocampus and hypothalamic-pituitary axis. Thirteen patients with limited-stage small cell lung cancer were enrolled in this study. The hippocampus, hypothalamus, and pituitary gland were contoured based on T1-weighted magnetic resonance imaging. The prescribed dose to the whole brain planning target volume was 25 Gy in 10 fractions. Two treatment plans using equispaced coplanar intensity-modulated radiotherapy (IMRT) were generated: WBRT with hippocampus avoidance (H-A) and WBRT with hippocampus, hypothalamus, and pituitary gland avoidance (H-HP-A). Both "H-A" and "H-HP-A" plans successfully protected the hippocampus, which received mean doses of 9.1 and 9.6 Gy, respectively (p = 0.0002), whereas the "H-HP-A" plan decreased the doses to both the hypothalamus (mean dose 11.06 Gy) and the pituitary gland (mean dose 10.66 Gy). Both "H-A" and "H-HP-A" plans showed similar target coverage of 95.1%. The homogeneity index of the "H-A" plan was slightly better than that of the "H-HP-A" plan (0.20 vs 0.23, p= 0.0012). In conclusion, the use of equispaced coplanar IMRT was found to simultaneously protect the hippocampus and hypothalamic-pituitary axis while delivering WBRT with acceptable target coverage and homogeneity.

CK19 mRNA expression measured by reverse-transcription polymerase chain reaction (RT-PCR) in the peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation: an independent prognostic factor.

PURPOSE: To investigate the prognostic significance of circulating cancer cells in peripheral blood (PB) of patients with non-small cell lung cancer (NSCLC) treated by chemo-radiation with curative intent. METHODS: Cytokeratin-19 (CK19) mRNA was measured by nested reverse-transcription polymerase chain reaction (RT-PCR) in PB from 67 NSCLC patients before and after chemo-radiation. The measurements of CK19 mRNA were compared to the outcome of therapy to evaluate its significance of prognoses. RESULTS: The sensitivity and specificity of CK19 RT-PCR was 10(-7) and 96.7%, respectively. The positive rate of CK19 mRNA in PB before chemo-radiation was correlated only to N stage (p=0.014). In contrast, it was more closely correlated to histological types (adenocarcinoma versus non-adenocarcinoma) (p=0.019), weight loss (p=0.010), KPS status (p=0.027) and N stage (p=0.032) after chemo-radiation. CK19 status in PB before chemo-radiation did not permit predictions of overall survival (p=0.375) and progression-free survival (p=0.573). However, the patients with CK19 mRNA expression in PB after treatments had poorer overall survival (p<0.001) and progression-free survival (p<0.001) as compared to those with negative CK19 mRNA expression. The worst survivals were seen in patients with persistently positive CK19 mRNA expression both before and after treatments. Multivariate analyses demonstrated that the positivity of CK19 mRNA after chemo-radiation was an independent unfavorable prognostic factor for both overall survival and progression-free survival (p<0.001 and <0.001). CONCLUSION: Only after chemo-radiation could the measurement of CK19 mRNA in PB predict the prognoses of NSCLC. Patients with the positive CK19 mRNA had shorter survival compared to the negative patients.

[Detection and prognostic significance of micrometastasis in peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation therapy].

OBJECTIVE: To investigate the prognostic significance of micrometastasis (MM) in peripheral blood of patients with non-small cell lung cancer (NSCLC) treated by chemo-radiation therapy. METHODS: Peripheral blood was taken from 67 NSCLC patients before and after definitive chemo-radiation therapy. CK19 mRNA of the peripheral blood was measured by nested RT-PCR and both their relationship with clinicopathological features and prognostic significance were further investigated. RESULTS: The micrometastasis-positive rates were 65.7% (44/67) and 32.8% (22/67), respectively, before and after the treatment. The micrometastasis-positive rate before treatment was closely in correlation with N-stage (P = 0.014). In contrast, it turned out to be more closely related with histological types (P = 0.019), weight loss (P = 0.01), KPS status (P = 0.027) as well as N-stage (P = 0.032) after chemo-radiation therapy. 4-yr distant metastasis rates (DMR) for micrometastasis-positive and -negative patients were 78.3% and 70.4%, respectively, before the treatment (P = 0.544) while they were 100% and 62.9%, respectively, after the chemoradiation (P < 0.001). The median survival time (MST) and 4-yr overall survival rate (OSR) for pretreatment micrometastasis-positive and -negative patients were 13.8 months and 17.6 months, and 18.2% and 17.4%, respectively (P = 0.619), while for post-treatment micrometastasis-positive and -negative patients they were 7.8 months and 27.6 months and 0 and 26.4%, respectively (P < 0.001). Multivariate analysis showed that the post-treatment positive micrometastasis was an independent unfavorable prognostic factor (P = 0.000). CONCLUSION: Detection of micrometastasis in peripheral blood may possess a prognostic significance after definitive chemo-radiation therapy. Micrometastasis-negative patients have better prognosis compared to those with positive micrometastasis.

Electroacupuncture Improves Cognitive Function and Hippocampal Neurogenesis after Brain Irradiation.

Cognitive impairments after brain irradiation seriously affect quality of life for patients, and there is currently no effective treatment. In this study using an irradiated rat model, the role of electroacupuncture was investigated for treatment of radiation-induced brain injury. Animals received 10 Gy exposure to the entire brain, and electroacupuncture was administered 3 days before irradiation as well as up to 2 weeks postirradiation. Behavioral tests were performed one month postirradiation, and rats were then sacrificed for histology or molecular studies. Electroacupuncture markedly improved animal performance in the novel place recognition test. In the emotion test, electroacupuncture reduced defecation during the open-field test, and latency to consumption of food in the novelty suppressed feeding test. Brain irradiation inhibited the generation of immature neurons, but did not cause neural stem cell loss. Electroacupuncture partially restored hippocampal neurogenesis. Electroacupuncture decreased the amount of activated microglia and increased resting microglia in the hippocampus after irradiation. In addition, electroacupuncture promoted mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In conclusion, electroacupuncture could improve cognitive function and hippocampal neurogenesis after irradiation, and the protective effect of electroacupuncture was associated with the modulation of microglia and upregulation of BDNF in the hippocampus.

Hypo- or conventionally fractionated radiotherapy combined with chemotherapy in patients with limited stage small cell lung cancer.

BACKGROUND: Previous data from our institution showed that hypofractionated thoracic radiotherapy (HypoTRT) with concurrent etoposide/platinum chemotherapy yielded favorable survival in patients with limited-stage small cell lung cancer (LS-SCLC). The present study retrospectively compared the survival outcomes, failure patterns and toxicities between groups of LS-SCLC patients treated with conventionally fractionated thoracic radiotherapy (ConvTRT) or HypoTRT combined with chemotherapy. METHODS: Medical records of LS-SCLC patients between January 2010 and December 2013 at Fudan University Shanghai Cancer Center were retrospectively reviewed. All patients treated with chemotherapy and ConvTRT (2 Gy per fraction daily, DT ≥ 56 Gy) or HypoTRT (2.5 Gy per fraction daily, DT = 55 Gy) were eligible for analysis. Progression-free survival (PFS) and overall survival (OS) were generated for different populations using the Kaplan-Meier method and compared using the log-rank test. Comparisons of failure patterns and toxicity were analyzed using the χ 2 test. RESULTS: A total of 170 patients treated with HypoTRT (n = 69) or ConvTRT (n = 101) were eligible for analysis. The median PFS and OS were 13.7 and 25.3 months, respectively, in the ConvTRT cohort, which was similar to the HypoTRT cohort (PFS 18.2 months, p = 0.991, and OS 27.2 months, p = 0.698), with a median follow-up of 30 months. Multivariate analysis revealed that PCI and TNM stage were prognostic factors for PFS and that PCI was prognostic for OS. The patterns of failure (stratified by local-regional recurrence, distant metastasis or both as first relapse) were similar between the dose cohorts (p = 0.693, p = 0.330, p = 0.572). Distant metastasis remained the main failure pattern. The brain was the most frequent remote failure site, followed by bone, liver and adrenal gland. PCI improved the 2-year survival rate from 46.1% to 70.0% and the 2-year PFS rate from 20.9% to 45.3%, respectively (p < 0.001). Grade ≥3 esophagitis and pneumonitis occurred in 9.9% and 11.9%, respectively, of the patients in the ConvTRT cohort and in 11.6% and 10.0%, respectively, of those in the HypoTRT cohort (p = 0.815). CONCLUSION: This retrospective analysis demonstrated that HypoTRT or ConvTRT combined with etoposide/platinum chemotherapy yielded statistically similar survival, treatment failure outcomes, and toxicity profiles. PCI correlated with improved PFS and OS.

Cisplatin/etoposide chemotherapy combined with twice daily thoracic radiotherapy for limited small-cell lung cancer: a clinical phase II trial.

PURPOSE: To fit the situation of developing countries, where supportive care is not sufficient, a modified combined therapy of cisplatin/etoposide (EP) and hyperfractionated accelerated radiation therapy (HART) was conducted as a Phase II trial for limited-stage small-cell lung cancer (LSCLC) to evaluate the feasibility, toxicity, and tolerance of the combined therapy and to observe its efficacy and patterns of failure. METHODS AND MATERIALS: Chemotherapy and radiation were sequentially administered in 1 to 3 cycles before and 3 to 5 cycles after HART. Chemotherapy contained cisplatin in doses of 25 to 30 mg/m(2) from Day 1 to Day 3 and etoposide in doses of 50 to 70 mg/m(2) from Day 1 to Day 3. The HART schedule consisted of radiation delivered in 1.4-Gy fractions, twice a day, at intervals longer than 6 h for 5 treatment days a week, to a total dose of 56 Gy in 40 fractions over 4 weeks. RESULTS: From June 1997 to December 2000, 57 eligible patients were registered for this trial. All were limited stage, and the median age was 60 years (range, 25 to 70 years). Of the 57 patients, 3 were withdrawn because of distant metastases (1 case), Grade (Gr) III thrombocytopenia (1 case), and financial problems (1 case). Fifty-four patients completed the planned combined treatment. A median of 6 cycles of chemotherapy (range, 5-8 cycles) was administered during a median interval of 4.9 weeks (range, 3.0-8.9 weeks), and a radiation dose of 56 Gy in 40 fractions was delivered over 29 days. The most common acute complication was radiation esophagitis, which occurred in 41 cases (72%), 4 with Gr III. Thirty-six patients (64%) had acute pulmonary toxicity, 2 with Gr III. The median survival time was 24 months (95% CI, 21-28 months). The 1-year, 2-year, and 3-year survival rates were 81% (95% CI, 70%-91%), 49% (95% CI, 36%-62%), and 21% (95% CI, 10%-32%), respectively. Of 57 patients, 13 had locoregional progression. Nine patients failed inside radiation fields and 4 patients failed outside. The 1-year, 2-year, and 3-year locoregional progression-free survival rates were 85% (95% CI, 75%-95%), 74% (95% CI, 61%-87%), and 68% (95% CI, 52%-84%), respectively. Forty-four patients suffered distant metastases, 66% of which were in brain. The 1-year, 2-year, and 3-year distant metastasis rates were 31% (95% CI, 19%-43%), 59% (95% CI, 46%-72%), and 79% (95% CI, 68%-91%), respectively. CONCLUSIONS: The study led to the following conclusions: (1) LSCLC patients tolerate HART at 56 Gy in 40 fractions over 4 weeks combined with 6 cycles of EP chemotherapy. (2) Both control of the tumor in the thorax and survival appear superior to conventional fractionated radiation but not as good as that in a study by Turrisi and colleagues. (3) This modified chemoradiation schedule could be recommended to LSCLC patients in developing countries. (4) The lessons learned from our study are (a) higher radiation doses may be needed for better locoregional control, and (b) prophylactic cranial irradiation is necessary for LSCLC patients who show complete response.

Phase 2 study of accelerated hypofractionated thoracic radiation therapy and concurrent chemotherapy in patients with limited-stage small-cell lung cancer.

PURPOSE: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. METHODS AND MATERIALS: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. RESULTS: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. CONCLUSION: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

Electroacupuncture prevents cognitive impairments by regulating the early changes after brain irradiation in rats.

Cognitive impairments severely affect the quality of life of patients who undergo brain irradiation, and there are no effective preventive strategies. In this study, we examined the therapeutic potential of electroacupuncture (EA) administered immediately after brain irradiation in rats. We detected changes in cognitive function, neurogenesis, and synaptic density at different time points after irradiation, but found that EA could protect the blood-brain barrier (BBB), inhibit neuroinflammatory cytokine expression, upregulate angiogenic cytokine expression, and modulate the levels of neurotransmitter receptors and neuropeptides in the early phase. Moreover, EA protected spatial memory and recognition in the delayed phase. At the cellular/molecular level, the preventative effect of EA on cognitive dysfunction was not dependent on hippocampal neurogenesis; rather, it was related to synaptophysin expression. Our results suggest that EA applied immediately after brain irradiation can prevent cognitive impairments by protecting against the early changes induced by irradiation and may be a novel approach for preventing or ameliorating cognitive impairments in patients with brain tumors who require radiotherapy.

Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial.

PURPOSE: A prospective Phase I/II dose escalation study was conducted to determine the maximum tolerated dose (MTD) in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: MTD would be reached via a dose escalation study. After 42 Gy/21 fractions, 4.2 weeks by conventional fractionated irradiation through anteroposterior/posteroanterior fields, the 3D-CRT technique was used as boost. The planned total dose escalation depended on lung volume irradiated. According to the percentage of lung volume receiving >20 Gy, the patients were divided into three subgroups (i.e., <25%, 25%-37%, and >37%). The scheduled dose escalation began with 69 Gy and continued to 78 Gy. The boost doses were delivered at 3 Gy per fraction, once per day, five fractions per week. Each dose level includes 5 patients. Besides radiotherapy, all patients received neoadjuvant and adjuvant chemotherapy with MVP regimen (Mitomycin, Vindesine, cis-platium). The criterion for stopping further dose escalation was > or =20% of patients with > or =RTOG Grade 3 radiation pneumonitis. RESULTS: Between June 1999 and February 2001, 50 patients had been enrolled in this study, including 4 with Stage II disease, 31 with Stage IIIa disease, and 15 with Stage IIIb disease. The dose escalation plan has been completed. All subgroups reached the highest predetermined dose levels (i.e., 78 Gy for the <25% subgroup, 78 Gy for the 25-37% subgroup, and 75 Gy for the >37% subgroup). Although none of the subgroups developed more than 20% of >/=Grade 3 acute pneumonitis, dose escalation was terminated because long-term follow-up was needed to observe late complications. Median follow-up time (MFT) for the entire group was 18 months (6-37 months). The most common acute complication was esophagitis in 56% of patients with RTOG Grade 1-2, and in 4% with Grade 3. Acute radiation pneumonitis developed in 36% of patients with RTOG Grade 1-2. Only 1 patient had Grade 3 pneumonitis, which was in the 25-37% subgroup at 75 Gy. The hematopoietic toxicity appeared in 58% of patients with Grade 1-2, and 8% with Grade 3. As to late complications, only 30% of patients developed pulmonary fibrosis of RTOG Grade 1-2. The median survival time for the entire group was 18 months. Two-year overall survival, locoregional progression-free rate, and distant metastasis rate were 44%, 40%, and 41%, respectively. CONCLUSIONS: Although MFT was 18 months, it had not yet been declared because a longer follow-up was needed to observe the late complications. The 2-year overall survival of 44% was very encouraging and implied that 3D-CRT combined with chemotherapy would improve the outcome for locally advanced NSCLC.