Does adjuvant radiotherapy benefit patients with diffuse-type gastric cancer? Results from the Surveillance, Epidemiology, and End Results database.

BACKGROUND: Diffuse-type gastric cancer is observed in approximately one-third of gastric cancers, yet the optimal treatment remains controversial. In the recently published Intergroup 0116 trial, a subgroup analysis demonstrated a lack of a long-term survival benefit for adjuvant chemoradiation therapy among patients with diffuse-type gastric cancer. METHODS: The Surveillance, Epidemiology, and End Results registry database was queried for patients who were newly diagnosed with diffuse-type gastric cancer between 2002 and 2005 and underwent surgical resection with or without adjuvant radiotherapy (RT). Overall survival (OS) was analyzed by the Kaplan-Meier method. Cox proportional hazards models were used to investigate the association between adjuvant RT and OS, with and without adjusting for other factors. In addition, propensity score methods were used to control for the possible effects of measured confounders. RESULTS: A total of 1889 cases of surgically resected diffuse-type gastric cancer were included in the analysis; of these cases, 782 patients received adjuvant RT and 1107 did not receive RT. The median survival time was 30 months in the group treated with adjuvant RT versus 18 months in the group that did not receive RT with matched propensity scores (P<.001). The Cox model confirmed the improvement in OS in patients who received adjuvant RT (hazard ratio, 0.75; 95% confidence interval, 0.65-0.82 [P<.001]). CONCLUSIONS: The current population-based observational study suggested a potential survival benefit for adjuvant RT among patients with diffuse-type gastric cancer. The standard treatment will likely remain controversial until evidence becomes available from phase 3 randomized trials exclusively for patients with diffuse-type gastric cancer.

Patterns of care for locally advanced vulvar cancer.

OBJECTIVE: Patients with locally advanced vulvar carcinoma can be treated with primary surgery or neoadjuvant chemoradiation. Neoadjuvant treatment appears to be associated with decreased morbidity and acceptable long-term outcomes. We examined the patterns of care for women with locally advanced vulvar cancer. STUDY DESIGN: Data from the Surveillance, Epidemiology, and End Results (SEER) database was used to examine women with stage III-IVA vulvar cancer treated from 1988 to 2008. Primary therapy was classified as surgery or radiation. Multivariable logistic regression models were developed to examine the use of primary radiotherapy. RESULTS: We identified a total of 2292 women including 1757 who underwent primary surgery (76.7%) and 535 treated with primary radiation (23.3%). The use of primary radiation increased with time from 18.0% in 1988 to 30.1% in 2008. In a multivariable model, older women (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.03-1.72), black women (OR, 1.59; 95% CI, 1.14-2.23), and patients with stage IVA tumors (OR, 2.23; 95% CI, 1.78-2.81) were more likely to receive primary radiation. Among women treated with primary radiotherapy, only 17.8% ultimately underwent surgical resection. CONCLUSION: The use of primary radiation for locally advanced vulvar cancer is limited but has increased over time. Multiple patient and tumor factors influence use. The majority of patients with stage III-IVA vulvar cancer treated with primary radiation therapy did not undergo surgical resection.

Patterns of care and treatment outcomes for elderly women with cervical cancer.

BACKGROUND: Cervical cancer is common in the elderly. The authors examined the patterns of care, treatment, and outcomes of elderly women with cervical cancer. METHODS: Women with cervical cancer diagnosed between 1988 and 2005 and registered in the Surveillance, Epidemiology, and End Results database were analyzed. Patients were stratified by age: <50, 50 to 59, 60 to 69, 70 to 79, and ≥80 years. Multivariate logistic regression models were constructed to examine treatment; cancer-specific survival was examined using Cox proportional hazards models. RESULTS: A total of 28,902 women were identified, including 2543 women 70 to 79 years old and 1364 ≥80 years. For women with early stage (IB1-IIA) tumors, primary surgery was performed in 82.0% of women <50 years old compared with 54.5% of those 70 to 79 years old and 33.2% of those ≥80 years old (P < .0001). For women treated surgically, lymphadenectomy was performed in 66.8% of women <50 years old versus 9.1% of patients ≥80 years old (P < .0001). Compared with patients <50 years old, those >80 years old were less likely to undergo radical hysterectomy (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.07-0.14) and lymphadenectomy (OR, 0.11; 95% CI, 0.08-0.16) and to receive adjuvant radiation therapy (OR, 0.06; 95% CI, 0.01-0.35). Among women with stage IIB-IVA disease, use of brachytherapy declined with age (P < .0001). For women with stage IB1-IIA tumors, the hazard ratio for death from cancer was 1.35 (95% CI, 1.16-1.58) for women 70 to 79 years old and 2.08 (95% CI, 1.72-2.48) for those ≥80 years old compared with younger women. CONCLUSIONS: Elderly women with cervical cancer are less likely to undergo surgery, receive adjuvant radiation, and receive brachytherapy. After adjusting for treatment disparities, cancer-specific mortality is higher in older women.

Lymphadenectomy influences the utilization of adjuvant radiation treatment for endometrial cancer.

OBJECTIVE: We analyzed the effect of lymphadenectomy on the use of adjuvant radiation treatment for women with stage I-II endometrial cancer. STUDY DESIGN: Women with stage I-II endometrioid adenocarcinomas treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were identified. The influence of lymphadenectomy (LND) on receipt of external beam radiation and brachytherapy stratified was examined. RESULTS: We identified 58,776 women including 26,043 who underwent LND (44.3%). Among women younger than 60 years of age with stage IA (grades 1, 2, and 3) tumors, LND had no impact on the use of radiation. Patients with stage IB (grade 2 or 3) and stage IC (grade 1 or 2) tumors who underwent lymph node dissection were less likely to undergo external beam radiation and more likely to receive vaginal brachytherapy (P < .05 for all). Furthermore, the extent of lymphadenectomy influenced the receipt of radiation. CONCLUSION: Women who undergo lymphadenectomy are less likely to receive whole pelvic radiotherapy.

Down-regulation of microRNA 106b is involved in p21-mediated cell cycle arrest in response to radiation in prostate cancer cells.

BACKGROUND: microRNAs (miRNAs) are endogenous short non-coding RNAs, and play a pivotal role in regulating of a variety of cellular processes, including proliferation and apoptosis, both of which are cellular responses to radiation treatment. The purpose of this study is to identify candidate miRNAs whose levels are altered in response to radiation in prostate cancer cells and to investigate the molecular pathway of such miRNAs in the regulation of radiation-induced cellular response. METHODS: Using a miRNA microarray assay, we screened 132 cancerous miRNAs in LNCaP cells in response to radiation treatment. The function of one candidate miRNA was investigated for checkpoint protein expression, cell cycle arrest, cell proliferation, and cell survival in cells transfected with precursor or antisense miRNA. RESULTS: In response to radiation, multiple miRNAs, including mi-106b, showed altered expression. Cells transfected with precursor miR-106b were able to suppress radiation-induced p21 activation. Functionally, exogenous addition of precursor miR-106b overrode the G2/M arrest in response to radiation and resulted in a transient diminishment of radiation-induced growth inhibition. CONCLUSION: We have shown a novel role of miR-106b, in the setting of radiation treatment, in regulating the p21-activated cell cycle arrest. Our finding that miR-106b is able to override radiation-induced cell cycle arrest and cell growth inhibition points to a potential therapeutic target in certain prostate cancer cells whose radiation resistance is likely due to consistently elevated level of miR-106b.

Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22).

PURPOSE: To assess the results of a multi-institutional study of intensity-modulated radiation therapy (IMRT) for early oropharyngeal cancer. PATIENTS AND METHODS: Patients with oropharyngeal carcinoma Stage T1-2, N0-1, M0 requiring treatment of the bilateral neck were eligible. Chemotherapy was not permitted. Prescribed planning target volumes (PTVs) doses to primary tumor and involved nodes was 66 Gy at 2.2 Gy/fraction over 6 weeks. Subclinical PTVs received simultaneously 54-60 Gy at 1.8-2.0 Gy/fraction. Participating institutions were preapproved for IMRT, and quality assurance review was performed by the Image-Guided Therapy Center. RESULTS: 69 patients were accrued from 14 institutions. At median follow-up for surviving patients (2.8 years), the 2-year estimated local-regional failure (LRF) rate was 9%. 2/4 patients (50%) with major underdose deviations had LRF compared with 3/49 (6%) without such deviations (p = 0.04). All cases of LRF, metastasis, or second primary cancer occurred among patients who were current/former smokers, and none among patients who never smoked. Maximal late toxicities Grade >or=2 were skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Longer follow-up revealed reduced late toxicity in all categories. Xerostomia Grade >or=2 was observed in 55% of patients at 6 months but reduced to 25% and 16% at 12 and 24 months, respectively. In contrast, salivary output did not recover over time. CONCLUSIONS: Moderately accelerated hypofractionatd IMRT without chemotherapy for early oropharyngeal cancer is feasible, achieving high tumor control rates and reduced salivary toxicity compared with similar patients in previous Radiation Therapy Oncology Group studies. Major target underdose deviations were associated with higher LRF rate.

Cyclin D1 guanine/adenine 870 polymorphism with altered protein expression is associated with genomic instability and aggressive clinical biology of esophageal adenocarcinoma.

PURPOSE: Altered cyclin D1 (CD1), a cell cycle regulator, may play an important role in imparting aggressive nature to esophageal adenocarcinoma (EAC). CD1 gene single nucleotide polymorphism G/A870 results in two alternatively spliced transcripts, CD1a and CD1b. CD1b, preferentially encoded by the A870 allele, is putatively oncogenic. We hypothesized that CD1 A870 allele would be associated with higher CD1 protein expression, and increased genomic instability during EAC evolution, leading to more aggressive phenotype. PATIENTS AND METHODS: One hundred twenty-four archival specimens of EAC, and 39 associated Barrett's esophagus (BE) specimens were examined for CD1 genotype, CD1 protein expression, and chromosome 9 polysomy (representing genomic instability). We correlated CD1 genotypes with CD1 protein expression, genomic instability, age at diagnosis of EAC, and overall survival (OS). RESULTS: The A870 allele was associated with higher levels of CD1 protein expression in EAC (P = .032); in BE (P = .01) where it was associated with concomitant increased chromosome 9 polysomy (P = .002); and with a younger age at diagnosis (P < .001) and poor OS (P = .0003) of EAC patients. CONCLUSION: Our data suggest that CD1 A870 background may be imparting aggressive phenotype to EAC. It provides a molecular basis to explain the clinical biology associated with CD1 polymorphism whereas aberrant nuclear accumulation of CD1 protein enhances the acquisition of genomic instability (ie, clonal diversity), thus leading to early age of EAC diagnosis and poor OS. CD1 genotyping with other biomarkers may help create a biomarker-based prognostic model for EAC and CD1 may also serve as a therapeutic target.

Pretherapy nuclear factor-kappaB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma.

BACKGROUND: Transcriptional factor nuclear factor-kappaB (NF-kappaB) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-kappaB would define clinical biology irrespective of the type of chemotherapy or sequence administered. METHODS: Pretherapy and/or posttherapy cancer specimens were examined for activated NF-kappaB and correlated with pathologic response to chemoradiation, metastatic potential, overall survival, disease-free survival, and type of chemotherapy or sequence used. FINDINGS: Eighty patients undergoing chemotherapy and concurrent radiation were studied. Activated NF-kappaB prior to any therapy was associated with the lack of complete pathologic response (pathCR, P = 0.006). Forty-five (78%) of 58 patients achieving

Effects of external beam radiation in the rat tibial nerve after crush, transection and repair, or nerve isograft paradigms.

INTRODUCTION: In head and neck surgery, radiation therapy is often administered to an injured nerve. Previous studies have examined the effects of either preoperative or postoperative radiation on nerve regeneration in rodents. In these studies, histomorphometric analysis was performed up to 8 month postoperatively. Given the exceptional neuroregenerative capacity of rodents, significant differences in nerve regeneration may go undetected if nerves are evaluated at such distant postoperative time points. This study is designed with a more appropriate model and investigates the effects of radiation after three common nerve injury paradigms. METHODS: Sixty-four Lewis rates were randomized to 8 groups corresponding to uninjured, tibial nerve crush, transection and repair, or reconstruction with isografts. Half of the animals in each of these paradigms (n = 8 per group) were treated with 10 Gy of external beam radiation to the site of nerve injury at 7 days postoperatively. On postoperative day 28, functional recovery and histomorphometric assessment was performed. RESULTS: For a given paradigm of nerve injury, no significant differences in nerve fiber number, neural density, neural debris, or fiber width were noted between the control and radiated groups, and radiation did not affect functional recovery. CONCLUSION: Radiation had no discernible effect on nerve regeneration or functional recovery in the rodent nerve injury models studied. All assessments were made at time points suitable for detecting differences in nerve regeneration between groups. These findings suggest that administration of radiation to fields containing injured peripheral nerve is unlikely to adversely affect functional outcomes.

Functional imaging in treatment planning in radiation therapy: a review.

The remarkable technical developments obtained in radiation oncology have resulted in an increasing use of image-based treatment planning in radiation therapy for three-dimensional and intensity modulated radiation therapy, stereotactic irradiation and image-guided brachytherapy. There has been increased use of computer-based record and verify systems as well as electronic portal imaging to enhance treatment delivery. From the data presented it is evident that PET scanning and other functional imaging techniques play a major role in the definition of tumor extent and staging of patients with cancer. The recent introduction of a combined CT and PET scanner will substantially simplify image acquisition and treatment planning.