To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC).
Eligibility ...criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients.
Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed.
Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC.
Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF‐1 activity have ...been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF‐1 is eagerly desired for the development of novel anti‐cancer strategies. The importance of oxygen‐dependent and ubiquitin‐mediated proteolysis of the regulatory subunit of HIF‐1 (HIF‐1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF‐1α may become stable and active even under normoxic conditions; for example, when disease‐associated genetic and functional alterations in some genes trigger the aberrant activation of HIF‐1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.
This article reviews the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms.
Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent ...laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO2<0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well‐oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia‐targeting protein drug, TOP3, with which we have sought to address the above three difficulties.
To investigate the impact of pre-existing radiological interstitial lung disease (ILD) findings on the incidence of radiation pneumonitis (RP) and clinical outcomes after stereotactic body radiation ...therapy (SBRT) for stage I non–small-cell lung cancer.
We included 157 consecutive patients who underwent SBRT alone for stage I non–small-cell lung cancer and whose pretreatment lung computed tomography images were available for retrospective review. The pretreatment computed tomography images were evaluated retrospectively for the presence of ILD. The incidence of RP, overall survival (OS) rate, and the incidence of disease progression and local progression were evaluated between patients with ILD (ILD+) and without ILD (ILD−).
Pre-existing ILD was identified in 20 patients. The median follow-up period was 39.5 months. The incidences of RP worse than grade 2 (≥ Gr2 RP) and worse than grade 3 (≥ Gr3 RP) were significantly higher in ILD(+) than ILD(−) (1 year ≥ Gr2 RP rate, 55.0% versus 13.3%; p < 0.001 and 1year ≥ Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for ≥ Gr2 and ≥ Gr3 RP, and the volume of the irradiated lung. The OS rate tended to be worse in ILD(+) than ILD(−) (3-year OS, 53.8% versus 70.8%; p = 0.28). No difference was observed in the disease progression or local progression rates.
Pre-existing ILD was a significant risk factor for symptomatic and severe RP. Prescreening for ILD findings is important for determining the radiation pneumonitis risk when planning SBRT.
Microenvironment and Radiation Therapy Yoshimura, Michio; Itasaka, Satoshi; Harada, Hiroshi ...
BioMed research international,
01/2013, Volume:
2013
Journal Article
Peer reviewed
Open access
Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome ...tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment.
Background Previous comparative reports of stereotactic body radiotherapy (SBRT) and surgery for non-small cell lung cancer (NSCLC) suffered from short follow-up, mixed extents of resection and ...inclusion of benign lesion. We aimed to make comparisons of long-term outcomes between a pure series of video-assisted thoracoscopic surgery (VATS) lobectomy and SBRT for biopsy-proven clinical stage I NSCLC. Methods We retrospectively compared overall survival (OS), cause-specific survival (CSS), recurrence-free survival (RFS), local control, regional lymph node (LN) control, and distant control between VATS lobectomy (n = 413) and SBRT (n = 104) for biopsy-proven clinical stage I NSCLC at our institution between 2003 and 2009. Propensity score matching was used to adjust the confounding effects in estimating treatment hazard ratios. Forty-one VATS lobectomy patients and 41 SBRT patients were matched blinded to outcome (1:1 ratio, caliper distance; 0.5). Results After propensity score matching, the follow-up period of the whole cohort ranged from 5 to 120 months with a median of 48. After propensity score matching there were significant differences in OS ( p = 0.0016), CSS ( p = 0.0015), RFS ( p < 0.0001), local control ( p = 0.0019), and distant control ( p < 0.0001) and no significant difference in regional LN control ( p = 0.11). The VATS lobectomy patients and SBRT patients had 68.5% and 37.3% of 5-year OS, 83.5% and 56.7% of 5-year CSS, and 60.4% and 19.5% of 5-year RFS, respectively. Conclusions Our results suggest VATS lobectomy may offer significantly more favorable long-term outcomes than SBRT in potentially operable patients with biopsy-proven clinical stage I NSCLC.
To review treatment outcomes for stereotactic body radiotherapy (SBRT) in medically operable patients with Stage I non-small-cell lung cancer (NSCLC), using a Japanese multi-institutional database.
...Between 1995 and 2004, a total of 87 patients with Stage I NSCLC (median age, 74 years; T1N0M0, n=65; T2N0M0, n=22) who were medically operable but refused surgery were treated using SBRT alone in 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. Total dose was 45-72.5 Gy at the isocenter, administered in 3-10 fractions. Median calculated biological effective dose was 116 Gy (range, 100-141 Gy). Data were collected and analyzed retrospectively.
During follow-up (median, 55 months), cumulative local control rates for T1 and T2 tumors at 5 years after SBRT were 92% and 73%, respectively. Pulmonary complications above Grade 2 arose in 1 patient (1.1%). Five-year overall survival rates for Stage IA and IB subgroups were 72% and 62%, respectively. One patient who developed local recurrences safely underwent salvage surgery.
Stereotactic body radiotherapy is safe and promising as a radical treatment for operable Stage I NSCLC. The survival rate for SBRT is potentially comparable to that for surgery.
Since 1998, we have treated primary and oligometastatic lung tumors with stereotactic body radiotherapy (SBRT). The term "oligometastasis" is used to indicate a small number of metastases limited to ...an organ. We evaluated our clinical experience of SBRT for oligometastatic lung tumors.
A total of 34 patients with oligometastatic lung tumors were included in this study. The primary involved organs were the lung (n = 15), colorectum (n = 9), head and neck (n = 5), kidney (n = 3), breast (n = 1), and bone (n = 1). Five to seven, noncoplanar, static 6-MV photon beams were used to deliver 48 Gy (n = 18) or 60 Gy (n = 16) at the isocenter, with 12 Gy/fraction within 4-18 days (median, 12 days).
The overall survival rate, local relapse-free rate, and progression-free rate at 2 years was 84.3%, 90.0%, and 34.8%, respectively. No local progression was observed in tumors irradiated with 60 Gy. SBRT-related pulmonary toxicities were observed in 4 (12%) Grade 2 cases and 1 (3%) Grade 3 case. Patients with a longer disease-free interval had a greater overall survival rate.
The clinical result of SBRT for oligometastatic lung tumors in our institute was comparable to that after surgical metastasectomy; thus, SBRT could be an effective treatment of pulmonary oligometastases.
Abstract Background The aim of this study was to perform a survival comparison between stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small-cell lung ...cancer (NSCLC) at high risk for lobectomy. Methods All patients who underwent SBRT or SLR because of medical comorbidities for clinical stage I NSCLC were reviewed retrospectively. Propensity score matching (PSM) was performed to reduce selection bias between SLR and SBRT patients based on age, gender, performance status, tumour diameter, forced expiratory volume in 1 second (FEV1) and Charlson comorbidity index (CCI). Results One hundred and fifteen patients who underwent SBRT and 65 SLR were enrolled. The median potential follow-up periods for SBRT and SLR were 6.7 and 5.3 years, respectively. No treatment-related deaths were observed. Before PSM, the 5-year overall survival (OS) was 40.3% and 60.5% for SBRT and SLR, respectively ( P = 0.008). PSM identified 53 patients from each treatment group with similar characteristics: a median age of 76 years, a performance status of 0–1, a median tumour diameter of ∼20 mm, a median FEV1 of ∼1.8 L and a median CCI of 1. The difference in OS became insignificant between the matched pairs (40.4% and 55.6% at 5 years with SBRT and SLR; P = 0.124). The cumulative incidence of cause-specific death was comparable between groups (35.3% and 30.3% at 5 years, P = 0.427). Conclusion SBRT can be an alternative treatment option to SLR for patients who cannot tolerate lobectomy because of medical comorbidities.
OBJECTIVE The aim of this systematic review was to provide an objective summary of the published literature pertaining to the use of stereotactic body radiation therapy (SBRT) specific to previously ...untreated spinal metastases. METHODS The authors performed a systematic review, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, of the literature found in a search of Medline, PubMed, Embase, and the Cochrane Library up to March 2015. The search strategy was limited to publications in the English language. RESULTS A total of 14 full-text articles were included in the analysis. All studies were retrospective except for 2 studies, which were prospective. A total of 1024 treated spinal lesions were analyzed. The median follow-up time ranged from 9 to 49 months. A range of dose-fractionation schemes was used, the most common of which were 16-24 Gy/1 fraction (fx), 24 Gy/2 fx, 24-27 Gy/3 fx, and 30-35 Gy/5 fx. In studies that reported crude results regarding in-field local tumor control, 346 (85%) of 407 lesions remained controlled. For studies that reported actuarial values, the weighted average revealed a 90% 1-year local control rate. Only 3 studies reported data on complete pain response, and the weighted average of these results yielded a complete pain response rate of 54%. The most common toxicity was new or progressing vertebral compression fracture, which was observed in 9.4% of cases; 2 cases (0.2%) of neurologic injury were reported. CONCLUSION There is a paucity of prospective data specific to SBRT in patients with spinal metastases not otherwise irradiated. This systematic review found that SBRT is associated with favorable rates of local control (approximately 90% at 1 year) and complete pain response (approximately 50%), and low rates of serious adverse events were found. Practice guidelines are summarized based on these data and International Stereotactic Radiosurgery Society consensus.
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