Prognostic impact of radiation therapy in tubular carcinoma of the breast.

PURPOSE: Tubular carcinoma (TC) is an invasive breast cancer with favorable prognosis. While pathology-specific guidelines exist for TC regarding adjuvant chemotherapy and endocrine therapy, no recommendations exist regarding locoregional treatment based on tumor histology. Prognostic impact of radiotherapy for patients with TC remains unclear. MATERIALS AND METHODS: The National Cancer Database was queried (2004-2015) for patients with pN0M0 TC who underwent lumpectomy. Chi-square testing compared categorized variables between those who did and did not receive radiotherapy. Kaplan-Meier analysis evaluated overall survival (OS). Cox proportional hazard analysis identified variables prognostic for OS. Patients were divided into age cohorts ≤60 years and >60 years. Propensity score matching (PSM) was utilized to create similar cohorts. RESULTS: 9705 patients met selection criteria; 6182 (75.1%) received radiotherapy while 2045 (24.9%) did not. After PSM, radiotherapy (HR 0.582; 95% CI 0.494-0.686) and endocrine therapy (HR 0.737; 95% CI 0.623-0.872) were favorable prognostic factors on multivariate Cox regression analysis while age > 60 years (HR 5.131; 95% CI 3.753-7.016), Black race (HR 1.445; 95% CI 1.016-2.055), and Charlson-Deyo comorbidity score > 0 (HR 1.708; 95% CI 1.403-2.079) were unfavorable prognostic factors. After PSM, 5-year OS was 91.7% for those who received radiotherapy and 84.5% for those who did not; 10-year OS was 76.1% and 64.1%, respectively (p < 0.001). CONCLUSION: This is the largest study to date on TC and the prognostic impact of adjuvant radiotherapy. Postoperative radiotherapy is a favorable prognostic factor for OS in patients with pN0M0 TC, suggesting adjuvant radiotherapy should remain standard of care in these patients.

Prognostic and predictive impact of MGMT promoter methylation in grade 3 gliomas.

BACKGROUND: Grade 3 gliomas are aggressive primary brain tumors. Promoter methylation of methyl guanine methyl transferase (MGMT) has been associated with a favorable prognosis in patients with glioblastoma, but the impact of MGMT promoter methylation in patients with grade 3 gliomas is less clear. The purpose of the present study was to evaluate the utilization of MGMT testing in patients with Grade 3 glioma, as well its prognostic and predictive value. METHODS: The National Cancer Database (NCDB) was queried (2004-2016) for patients with newly diagnosed grade 3 glioma without 1p19q codeletion. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. RESULTS: Of 20,488 total patients, 1,209 (5.0%) had MGMT testing. Of these patients, 561 (46.4%) were MGMT methylated (mMGMT), and 648 (53.6%) were MGMT unmethylated (uMGMT). mMGMT patients experienced greater median overall survival (OS) than both uMGMT patients as well as patients with no MGMT status reported (p < 0.05 for both). mMGMT was associated with improved OS for patients receiving adjuvant chemoradiation or adjuvant radiation, but not for patients receiving adjuvant chemotherapy or no adjuvant treatment. CONCLUSIONS: This is the largest study to date describing the utilization of and outcomes for mMGMT patients with grade 3 glioma. The present results demonstrate that mMGMT is a prognostic factor and possibly a predictive biomarker, and is currently under-utilized within the US. MGMT methylation status could be used to risk-stratify and select patients for treatment intensification. IMPORTANCE OF STUDY: The present study is the largest of its kind to examine the prognostic and predictive impact of MGMT methylation (mMGMT) amongst patients with Grade 3 Glioma. The results suggest that mMGMT is prognostic, as amongst all patients, mMGMT was associated with improved overall survival. These results also suggest that mMGMT is predictive, as patients treated with adjuvant chemoradiation or adjuvant radiation therapy did have improved overall survival with mMGMT, though there was no difference in overall survival observes amongst patients receiving adjuvant chemotherapy or those patients receiving no adjuvant treatment. The study also found that only 5% of patients nationwide with Grade 3 Glioma are tested for MGMT.

Management, outcomes, and prognostic factors of adult primary spinal cord gliomas.

PURPOSE: Primary spinal cord tumors are rare, particularly in the adult population, and national guidelines remain ambiguous with regard to management approaches. To address this knowledge gap, we evaluated management, outcomes, and prognostic factors of these neoplasms. METHODS: The National Cancer Database was queried (2004-2016) for newly-diagnosed, histologically-confirmed WHO grades I-III astrocytomas and glioblastoma. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. RESULTS: Of 1,033 subjects, 196 (19%) were pilocytic astrocytomas (PAs), 539 (52%) were grade II/III astrocytomas, and 298 (29%) were glioblastomas (GBMs). Respectively, 11%, 30%, and 27% did not undergo resection (biopsy only). RT was delivered to 27%, 54%, and 73%; chemotherapy was given to 5%, 21%, and 37%, respectively. The median OS was not reached for PAs, but was 101.2 months for grade II/III astrocytomas, and 23.9 months for GBMs (p < 0.001). Neither chemotherapy nor RT (or dose thereof) was associated with increased OS for grade II/III astrocytomas (p > 0.05 for all), though there was a trend toward improved OS with the use of chemotherapy for patients with GBM. Surgical resection was associated with improved OS for grade II/III astrocytomas and GBM (p < 0.05). Independent prognostic factors for survival in this cohort included histologic classification and resection (compared to biopsy only) (p < 0.05 for both). CONCLUSIONS: This study sheds light onto the management of these rare tumors; surgery was associated with OS benefit for patients with GBM and Grade II/III astrocytomas. Neither RT nor chemotherapy were associated with OS benefit. Although not implying causation, these data can be used to guide patient counseling and therapeutic approaches.

Prognostic role of chemotherapy, radiotherapy dose, and extent of surgical resection in adult medulloblastoma.

PURPOSE: Adult medulloblastoma is rare, and management is extrapolated from pediatric cases. This investigation evaluated the prognostic role of chemotherapy (and sequencing thereof), the degree of resection, and craniospinal irradiation (CSI) dose. METHODS: The National Cancer Database was queried for adult (age ≥18) medulloblastoma. Resection was coded as gross (GTR) or subtotal resection (STR) or biopsy only; concurrent chemoradiotherapy (CRT) was defined as receipt within 14 days of each other. Statistics included Kaplan-Meier overall survival (OS) analysis and Cox proportional hazards modeling. RESULTS: Of 1144 patients, 613 had coded surgical information; 242 (39%) did not undergo surgery, 277 (45%) underwent STR, and 94 (15%) had GTR. A total of 428 (37.4%) did not receive chemotherapy, 348 (30.4%) received sequential CRT, and 368 (32.2%) underwent concurrent CRT. Of the 711 patients with CSI dose information, 202 (28.4%) received 23-30 Gy CSI and 509 (71.6%) patients received 30-36 Gy. Median follow-up was 56.5 months. Extent of resection did not correlate with 10-year OS (74.2% biopsy only, 72.7% STR, 82.2% GTR, p > 0.05 all comparisons) or on Cox multivariate analysis. Chemotherapy was associated with higher OS (65.6% vs. 51.2%, p = 0.035) and a trend towards significance on multivariate assessment (p = 0.082). Sequencing of chemotherapy and CSI dose were not associated with OS (p > 0.05 for both). CONCLUSIONS: Although causation cannot be implied, neither the extent of resection nor CSI dose associated with OS in adult medulloblastoma. Chemotherapy could have utility in higher-risk patients; concurrent administration may not be beneficial, especially given therapy-induced neuro-cognitive sequelae.

Patterns of management and outcomes of unifocal versus multifocal glioblastoma.

BACKGROUND: Glioblastoma (GBM) presents as a solitary lesion (unifocal), or as multiple discrete lesions (multifocal). Multifocal GBM may have a worse prognosis as compared to unifocal GBM, but existing data are limited to small institutional series. The purpose of the present study was to evaluate demographic and clinical characteristics of patients with unifocal versus multifocal GBM to highlight demographic differences and clinical outcomes for two groups of patients. METHODS: The National Cancer Database (NCDB) was queried (2004-2016) for patients newly diagnosed with either unifocal or multifocal GBM. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. RESULTS: Of 45,268 total patients, 37,483 (82.8%) had unifocal GBM and 7,785 (17.2%) had multifocal GBM. Patients with unifocal GBM more frequently received gross total resection (GTR) (41.2% versus 25.8%, p < 0.001) and conventionally fractionated radiation therapy (RT) (48.2% versus 42.7%, p < 0.001). Patients with multifocal GBM had a higher rate of surgery with biopsy only (34.0% compared to 24.1%, p < 0.001). Median OS was 12.8 months versus 8.3 months (p < 0.001) for patients with unifocal GBM or multifocal GBM, respectively. On multivariate analysis, factors associated with improved OS included unifocal disease, MGMT methylation, RT use, and chemotherapy use. CONCLUSIONS: This is the largest study to date describing outcomes for patients with multifocal GBM, and it shows that multifocal GBM is associated with a decreased use both of GTR and conventionally fractionated RT, as well as worse median OS. Further research is needed to improve clinical outcomes for patients with multifocal GBM.

Postmastectomy radiation therapy for triple negative, node-negative breast cancer.

PURPOSE: The use of post-mastectomy radiation therapy (PMRT) for patients with node-negative, triple negative breast cancer (TNBC) is controversial. This study of a large, contemporary US database described national practice patterns and addressed the impact of PMRT on survival for patients with node-negative TNBC. METHODS: The National Cancer Data Base was queried (2004-2014) for women with non-metastatic TNBC with pT1-4N0M0 disease undergoing mastectomy. Use of PMRT was assessed. Multivariable logistic regression ascertained factors associated with PMRT use. The Kaplan-Meier analysis evaluated overall survival (OS) between patients managed with either PMRT or observation following mastectomy when stratifying by pT stage. Cox proportional hazards modeling determined variables associated with OS. RESULTS: A total of 14,464 patients met the selection criteria; of these, 1,569 (10.8%) received PMRT, whereas 12,895 (89.2%) did not receive PMRT. Use of PMRT varied significantly with pT stage, with only 5.7% of T1 patients undergoing PMRT, while 51.6% of patients with T3 disease underwent PMRT. Use of PMRT was associated with superior OS for patients with pT3 disease but not for patients with other T stages. Greater age was associated with decreased likelihood of PMRT use, while increased T stage and positive surgical margins were associated with use of PMRT. On multivariate analysis, increased age, T stage, and positive surgical margins were associated with worse OS. CONCLUSIONS: In the largest study to date evaluating the use of PMRT in patients with node-negative TNBC, the use of PMRT was low in patients with T1 and T2 disease. Additionally, while an OS benefit was observed with the use of PMRT in patients with T3 disease, there was no benefit with the use of PMRT in other T stage groups. Further prospective studies are recommended to further elucidate the benefit on PMRT in patients with node-negative TNBC.

The Role of Adjuvant Radiotherapy in the Treatment of Pleural Mesothelioma.

BACKGROUND: Pleural mesothelioma is a rare but aggressive form of cancer. Local recurrence represents the majority of treatment failures and overall survival (OS) outcomes remain dismal. Adding locoregional treatment with radiotherapy after surgical resection has been considered but its role remains uncertain. OBJECTIVE: The purpose of this study was to evaluate the outcomes of adjuvant radiation therapy (RT) for patients with malignant pleural mesothelioma. METHODS: The National Cancer Data Base (NCDB) was queried (2004-2013) for patients with malignant mesothelioma. Patients were divided into three groups: observation, surgery alone, and surgery followed by adjuvant RT. Statistics included Fisher's exact or Chi square tests to analyze categorical proportions between groups, Kaplan-Meier analysis to evaluate OS, and Cox proportional hazards modeling to determine variables associated with OS. Propensity matching was performed to make comparisons between homogenous groups. RESULTS: Overall, the surgery plus radiotherapy group had a higher median survival (21.4 months) compared with surgery alone (16.59 months) [p < 0.001]. RT was more likely to be delivered after extrapleural pneumonectomy than with lung-sparing surgical approaches. On multivariable analysis, receipt of surgery plus radiotherapy, chemotherapy administration, and higher socioeconomic status were associated with improved OS (p < 0.0001). After propensity matching, receipt of surgery plus radiotherapy and chemotherapy administration were still associated with improved OS (p < 0.05). CONCLUSIONS: In the treatment of malignant pleural mesothelioma, adjuvant radiotherapy after surgical intervention was associated with improved OS. This study is the largest study of adjuvant radiotherapy to date, and our findings highlight the need for additional prospective data.

Outcomes of pleomorphic lobular carcinoma versus invasive lobular carcinoma.

PURPOSE: Pleomorphic lobular carcinoma (PLC) is a rare histologic variant of invasive lobular carcinoma (ILC) that has been associated with worse clinical outcomes than classic ILC. Owing to its rarity, high-volume studies of its clinical characteristics and prognosis are lacking. The purpose of this study was to use a large, contemporary cancer database to investigate the clinical characteristics and survival outcomes for patients with PLC. METHODS: The National Cancer Database (NCDB) was queried for women with cT1-4N1-3M0 breast cancer with either ILC or PLC histology having received definitive surgical therapy. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier analysis evaluated overall survival (OS) between all patients and between patients when stratifying by age and subtype. Cox proportional hazards modeling determined variables associated with OS. RESULTS: A total of 115,260 patients met the study criteria; of these, 114,859 (99.6%) had ILC, while 401 (0.4%) had PLC. A greater proportion of patients with PLC had T3-4 and node-positive disease, and were more likely to have ER- and HER2+ disease. PLC histology was associated with worse OS on both univariate and multivariate analysis (p < 0.001). PLC was associated with poorer OS in subgroups that were T3-4/N+ (but not T1-2N0) disease and ER+ (but not ER-) cancers, but not by HER2 status. CONCLUSIONS: Patients with PLC, who were more likely to have ER- and HER2+ disease, experienced worse OS than patients with ILC, which may be limited to patients with more advanced clinical stage and ER + disease. Further work is needed to determine the optimal treatment for this more aggressive form of breast cancer.

Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy.

PURPOSE: This is the largest study to date evaluating response rates and pathologic complete response (pCR) and predictors thereof, based on molecular subtype, in women with breast cancer having undergone neoadjuvant chemotherapy (NC). METHODS: The National Cancer Database was queried for women with cT1-4N1-3M0 breast cancer having received NC. Patients were divided into four subtypes: luminal A, luminal B, Her2, or triple negative (TN). Multivariable logistic regression ascertained factors associated with developing pCR. Kaplan-Meier analysis evaluated overall survival (OS) between patients by degree of response to NC when stratifying patients by subtype. RESULTS: Of a total of 13,939 women, 322 (2%) were luminal A, 5941 (43%) luminal B, 2274 (16%) Her2, and 5402 (39%) TN. Overall, 19% of all patients achieved pCR, the lowest in luminal A (0.3%) and the highest in Her2 (38.7%). Molecular subtype was an independent predictor of both pCR and OS in this population. Clinical downstaging was associated with improved survival, mostly in women with luminal B, Her2, and TN subtypes. Subgroup analysis of the pCR population demonstrated 5-year OS in the luminal B, Her2, and TN cohorts of 93.0, 94.2, and 90.6%, respectively (Her2 vs. TN, p = 0.016). CONCLUSIONS: Assessing nearly 14,000 women from a contemporary United States database, this is the largest known study examining the relationship between response to NC and molecular subtype. Women with luminal A disease are the least likely to undergo pCR, with the highest rates in Her2 disease. Degree of response is associated with OS, especially in luminal B, Her2, and TN patients. Despite the comparatively higher likelihood of achieving pCR in TN cases, this subgroup may still experience a survival detriment, which has implications for an ongoing national randomized trial.

Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models.

OBJECTIVES: The objectives of this study are to explore the potential benefits of combining AdGlipr1 (or AdGLIPR1) gene therapy with radiotherapy using subcutaneous prostate and bladder cancer models. MATERIALS AND METHODS: Combination adenoviral vector-mediated gene therapy and radiotherapy were applied to 178-2 BMA and TSU-Pr1 cells in vitro and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and tumor growth suppression and survival extension were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/ßgal, as well as single-cycle treatment with 2-cycle treatment. RESULTS: Combination treatment significantly suppressed colony formation and increased apoptosis in vitro. In vivo, combination therapy produced significant 178-2 BMA and TSU-Pr1 tumor growth suppression and survival extension compared with the monotherapies or the control. Further tumor growth suppression and survival extension were observed after 2 cycles of the combination treatment. CONCLUSIONS: Combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or synergistic tumor control in selected prostate and bladder tumors, and additional therapeutic effects may result with repeated treatment cycles.