Faculty Bibliography

PURPOSE: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases. METHODS AND MATERIALS: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria. RESULTS: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors. CONCLUSION: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI.

PURPOSE: To determine a relationship between sexual functioning and health state among survivors of stage I endometrial cancer, and to examine whether adjuvant intravaginal radiotherapy (IVRT) affects these measures compared to hysterectomy alone. METHODS: Two hundred five survivors (>1 year from surgery) completed questionnaires containing the EuroQol (EQ5D) and the Female Sexual Function Index (FSFI). A total of 136 (66.3 %) underwent surgery alone, and 69 (33.7 %) received IVRT. Pearson correlation was used to correlate FSFI and EQ5D-Health State scores. Multivariable regression was performed to measure the impact of IVRT on sexual functioning and health state. RESULTS: A majority of patients (80 %) met criteria for sexual dysfunction by FSFI < 26.5. A significant correlation was detected between FSFI and EQ5D scores (Pearson correlation = 0.21, p = 0.003). Compared to the IVRT group, the surgery group was younger (p = 0.001) and trended toward more frequent use of minimally invasive surgery versus laparotomy (p = 0.08). Otherwise, the two groups were well balanced with respect to demographics, comorbidities, and baseline sexual activity. Controlling for age and surgery type, IVRT was not associated with poorer health state or sexual function. Receipt of laparotomy was associated with both poorer health state and sexual function (p = 0.0156 and p = 0.0247, respectively). CONCLUSIONS: Sexual functioning was generally poor among endometrial cancer survivors; however, those with improved FSFI scores tended to have superior health states. IVRT was not a significant risk factor; however, receipt of laparotomy appeared to be associated with poorer sexual functioning and health state.

PURPOSE/OBJECTIVES: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. METHODS AND MATERIALS: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. RESULTS: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). CONCLUSIONS: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-alpha (TGF-alpha) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-alpha/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-alpha in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-alpha secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-alpha converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and checkpoint kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-alpha partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-alpha autocrine loop following IR.

PURPOSE: Rhabdomyosarcoma (RMS) is a pediatric sarcoma rarely occurring in adults. For unknown reasons, adults with RMS have worse outcomes than do children. METHODS AND MATERIALS: We analyzed data from all patients who presented to Memorial Sloan-Kettering Cancer Center between 1990 and 2011 with RMS diagnosed at age 16 or older. One hundred forty-eight patients met the study criteria. Ten were excluded for lack of adequate data. RESULTS: The median age was 28 years. The histologic diagnoses were as follows: embryonal 54%, alveolar 33%, pleomorphic 12%, and not otherwise specified 2%. The tumor site was unfavorable in 67% of patients. Thirty-three patients (24%) were at low risk, 61 (44%) at intermediate risk, and 44 (32%) at high risk. Forty-six percent were treated on or according to a prospective RMS protocol. The 5-year rate of overall survival (OS) was 45% for patients with nonmetastatic disease. The failure rates at 5 years for patients with nonmetastatic disease were 34% for local failure and 42% for distant failure. Among patients with nonmetastatic disease (n=94), significant factors associated with OS were histologic diagnosis, site, risk group, age, and protocol treatment. On multivariate analysis, risk group and protocol treatment were significant after adjustment for age. The 5-year OS was 54% for protocol patients versus 36% for nonprotocol patients. CONCLUSIONS: Survival in adult patients with nonmetastatic disease was significantly improved for those treated on RMS protocols, most of which are now open to adults.

PURPOSE: We investigated the factors that influenced urinary symptoms in the first 10 years after prostate brachytherapy. MATERIALS AND METHODS: A total of 1,932 men were treated with prostate brachytherapy alone or with external beam irradiation and followed a mean of 6.8 years. The influence of pretreatment American Urological Association symptom score (7 or less, 8 to 19, 20 or greater), external beam radiotherapy, (125)I or (103)Pd, biological effective dose, age, prostate size and hormone therapy on the change in American Urological Association symptom score (11,491) was compared. RESULTS: The mean change from initial score (7.4) was 11.4, 5.5, 3.3, 2.7, 1.5, 1.2, 1, 1, 1, 1, 1.3 and 1.4 points at 3, 6 months and 1 to 10 years, respectively (p <0.001). Factors that resulted in a greater increase in urinary symptoms at year 1 were low pretreatment score (p <0.001), no hormonal therapy (p <0.001), younger age (p = 0.046) and higher biological effective dose (p = 0.025). At 10 years patients with an initial score of 20 or greater had an average decrease of 11 points compared to a decrease of 0.9 for an initial score of 8 to 19 and an increase of 2.7 for an initial score of 7 or less (p <0.001). On linear regression the scores at 1 year were influenced by initial score (p <0.001), biological effective dose (p = 0.022), prostate size (p <0.001) and hormonal therapy (p = 0.009). At 10 years only the pretreatment score remained significant (p <0.001). CONCLUSIONS: There is minimal change in mean American Urological Association symptom score (1.4 points) 10 years after prostate brachytherapy. Patients presenting with high initial scores have the greatest improvement from baseline. Biological effective dose, external beam radiotherapy, hormonal therapy, isotope, patient age and prostate size do not appear to influence long-term urinary symptoms.

PURPOSE: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. EXPERIMENTAL DESIGN: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. RESULTS: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. CONCLUSION: These data suggest that selumetinib can be used with 5-FU to augment radiation response.

Polyoma virus middle T antigen (PyVmT) is a powerful viral oncogene; however, the mechanisms of PyVmT activation are poorly understood. The insulin-like growth factor I receptor (IGF-IR) and the insulin receptor (IR) are known to be implicated in the development of many cancers. Furthermore, PyVmT-overexpressing mouse mammary carcinoma Met-1 cells are highly responsive to IGF-I and insulin. Herein, we demonstrate that PyVmT physically interacts with IGF-IR and IR in Met-1 cells. Insulin and IGF-I increase association of the IR and IGF-IR with PyVmT, enhance tyrosine phosphorylation of PyVmT and augment the recruitment of Src and PLCgamma(1) to PyVmT. This is accompanied by robust and sustained phosphorylation of Akt and ERK1/2, which are implicated in both PyVmT and IGF-IR/IR signalling. Both ligands significantly increase proliferation, survival, migration and invasion of Met-1 cells. Furthermore, orthotopic inoculation of Met-1 cells with shRNAmir-mediated knockdown of IR or IGF-IR fails to initiate tumour growth in recipient mice. In conclusion, our data indicate that the physical and functional interaction between PyVmT and cellular receptor tyrosine kinases, including IR and IGF-IR, is critical for PyVmT activation and tumour initiation. These results also provide a novel mechanism for oncogene activation in the host cell.