S.K. Cheng

Intensity-modulated radiation therapy for nasopharyngeal carcinoma: a review

IntroductionAdvances in radiation therapy, such as intensity-modulated radiation therapy (IMRT), have allowed high-dose delivery to tumors while sparing normal tissues. However, IMRT requires careful delineation of target volumes to prevent marginal recurrences.Results and discussionThis review discusses the recent advances in the treatment of nasopharyngeal carcinoma with particular emphasis on IMRT. Multiple phase III trials that have relied on conventional radiotherapy have shown a survival benefit to concurrent chemoradiotherapy (CCRT) over radiotherapy (RT) alone. Two randomized trials using IMRT have demonstrated decreased xerostomia rates compared to conventional radiotherapy while still maintaining excellent local control rates, although follow-up was short. While modern locoregional results are excellent, 90 % or more, distant-metastasis-free rates are not as impressive, ranging from 66 to 93 % among studies.ConclusionIMRT is an advanced technique, its excellent treatment outcomes have been reproduced in many single institution studies. Perhaps IMRT-delivered RT can replace the benefit provided by chemotherapy when added to conventional RT. Future studies should focus on reducing target volumes to minimize toxicity while dose-escalating for high-risk patients.

TGFBI expression reduces in vitro and in vivo metastatic potential of lung and breast tumor cells

Controversy has arisen as to the role of transforming growth factor-β-induced protein (TGFBI) in the regulation of tumor metastasis. Using lung and breast cancer cell lines (H522 and MCF-7, respectively), we established that TGFBI induced cell adhesion to extracellular matrix proteins by activating adhesion-associated signaling and subsequent structure reformation, ultimately leading to cells less motile; whereas TGFBI reduced abilities of colony formation in soft agar, penetration through matrix gel, and activation of matrix metalloproteinases 2 and 9. Furthermore, injection of TGFBI-expressing cells into immuno-deficient mice resulted in a significant reduction in tumor metastasis in vivo. Taken together, these data suggest that TGFBI moderates the metastatic potential of cancer cells.

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation

BACKGROUND We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC). METHODS A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population. RESULTS Median follow-up was 12 months. Median OS rates for the EGFR, KRAS, echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutated, and wild-type cohorts were 17, 7, 27, and 12 months, respectively (P = .019), and for targeted versus nontargeted therapy 21 and 11 months, respectively (P = .071). Targeted therapy was a strong predictor of increased OS on univariate (P = .037) and multivariate (P = .022) analysis. Gender, primary tumor controlled status, recursive partitioning analysis class, and graded prognostic assessment score were associated with OS (P < .05). On multivariate analysis, positive EGFR mutational status was a highly significant predictor for decreased survival (hazard ratio: 8.2; 95% CI: 2.0-33.7; P = .003). However, when we recategorized EGFR-mutant cases based on whether they received tyrosine kinase inhibitor, OS was no longer significantly shorter (hazard ratio: 1.5; P = .471). Median OS for patients with and without local failure was 17 and 12 months, respectively (P = .577). Local failure rates for EGFR, KRAS, EML4-ALK mutated, and wild-type cohorts by lesion were 8.7%, 5.4%, 4.3%, and 5.1%, respectively. CONCLUSIONS This study suggests that EGFR tyrosine kinase mutation and ALK translocation results in improved survival to targeted therapies and that mutation status itself does not predict survival and local control in patients with brain metastases from NSCLC.

Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells

Survival for lung cancer patients remains dismal and is largely attributed to treatment resistance. To identify novel target genes the modulation of which could modify platinum resistance, we performed a high-throughput RNAi screen and identified Yes-associated protein (YAP1), a transcription coactivator and a known oncogene, as a potential actionable candidate. YAP1 ablation significantly improved sensitivities not only to cisplatin but also to ionizing radiation, both of which are DNA-damaging interventions, in non-small cell lung cancer (NSCLC) cells. Overall YAP1 was expressed in 75% of NSCLC specimens, whereas nuclear YAP1 which is the active form was present in 45% of 124 resected NSCLC. Interestingly, EGFR-mutated or KRAS-mutated NSCLC were associated with higher nuclear YAP1 staining in comparison to EGFR/KRAS wild-type. Relevantly, YAP1 downregulation improved sensitivity to erlotinib, an EGFR inhibitor. A pharmacological inhibitor of YAP1 signaling, verteporfin also synergized with cisplatin, radiation and erlotinib in NSCLC cells by potentiating cisplatin and radiation-related double-stranded breaks and decreasing expression of YAP1 and EGFR. Taken together, our study is the first to indicate the potential role of YAP1 as a common modulator of resistance mechanisms and a potential novel, actionable target that can improve responses to platinum, radiation and EGFR-targeted therapy in lung cancer.

Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway

As an uncommon cancer, mesothelioma is very hard to treat with a low average survival rate owing to its usual late detection and being highly invasive. The link between asbestos exposure and the development of mesothelioma in humans is unequivocal. TGFBI, a secreted protein that is induced by transforming growth factor-β in various human cell types, has been shown to be associated with tumorigenesis in various types of tumors. It has been demonstrated that TGFBI expression is markedly suppressed in asbestos-induced tumorigenic cells, while an ectopic expression of TGFBI significantly suppresses tumorigenicity and progression in human bronchial epithelial cells. In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent. We observed that in the absence of TGFBI, the knockdown mesothelial and mesothelioma cell lines exhibited an elevated proliferation rate, enhanced plating efficiency, increased anchorage-independent growth, as well as an increased cellular protein synthesis rate as compared with their respective controls. Furthermore, cell cycle regulatory proteins c-myc/cyclin D1/phosphor-Rb were upregulated; a more active PI3K/Akt/mTOR signaling pathway was also detected in TGFBI-depleted cell lines. These findings suggest that TGFBI may repress mesothelioma tumorigenesis and progression via the PI3K/Akt signaling pathway.

Initial Clinical Experience Performing Patient Treatment Verification With an Electronic Portal Imaging Device Transit Dosimeter

PURPOSE To prospectively evaluate a 2-dimensional transit dosimetry algorithms performance on a patient population and to analyze the issues that would arise in a widespread clinical adoption of transit electronic portal imaging device (EPID) dosimetry. METHODS AND MATERIALS Eleven patients were enrolled on the protocol; 9 completed and were analyzed. Pretreatment intensity modulated radiation therapy (IMRT) patient-specific quality assurance was performed using a stringent local 3%, 3-mm γ criterion to verify that the planned fluence had been appropriately transferred to and delivered by the linear accelerator. Transit dosimetric EPID images were then acquired during treatment and compared offline with predicted transit images using a global 5%, 3-mm γ criterion. RESULTS There were 288 transit images analyzed. The overall γ pass rate was 89.1%±9.8% (average±1 SD). For the subset of images for which the linear accelerator couch did not interfere with the measurement, the γ pass rate was 95.7%±2.4%. A case study is presented in which the transit dosimetry algorithm was able to identify that a lung patients bilateral pleural effusion had resolved in the time between the planning CT scan and the treatment. CONCLUSIONS The EPID transit dosimetry algorithm under consideration, previously described and verified in a phantom study, is feasible for use in treatment delivery verification for real patients. Two-dimensional EPID transit dosimetry can play an important role in indicating when a treatment delivery is inconsistent with the original plan.

Timing of Adjuvant Radiotherapy in Glioblastoma Patients: A Single-Institution Experience With More Than 400 Patients.

BACKGROUND The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy (RT) and temozolomide (TMZ). OBJECTIVE To investigate whether the timing of adjuvant RT after surgery affected outcome in patients with GBM. METHODS We retrospectively reviewed all patients with a diagnosis of GBM at our institution. A total of 447 patients were included in our analysis. Patients were divided into 3 equal groups based on the interval between surgery and RT. The primary outcome was overall survival (OS). RESULTS Patients who began RT less than 21 days after surgery tended to be older, have a lower a Karnofsky Performance Status score, and higher recursive partitioning analysis class. These patients were more likely to have undergone biopsy only and received 3-dimensional conformal RT or 2-dimensional RT. The median OS for patients who started RT less than 21 days after surgery, between 21 and 32 days after surgery, and more than 32 days after surgery was 374, 465, and 478 days, respectively (P = .004). On multivariate Cox regression analysis, Karnofsky Performance Status score lower than 70, undergoing biopsy only, recursive partitioning analysis classes IV and V/VI, use of less than 36 Gy RT, and lack of TMZ chemotherapy were predictors of worse OS. The interval between surgery and RT was not significantly associated with OS on multivariate analysis. CONCLUSION Patients who begin RT less than 21 days after surgery tend to have worse prognostic factors than those who begin RT later. When accounting for significant covariates, the effect of timing between surgery and RT is not significant.

Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma

PURPOSE Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ. METHODS AND MATERIALS We conducted a retrospective analysis of patients ≥60 years of age with newly diagnosed GBM who received SFRT or HRT from 1994 to 2014 in the postoperative setting. Inclusion criteria included SFRT (60 Gy/30 fractions or 59.4 Gy/33 fractions) versus HRT (40 Gy/15 fractions). RESULTS In this cohort, 158 patients were treated with SFRT versus 26 with HRT. Median survival in patients receiving SFRT compared with HRT was 430 and 475 days (P = .550), respectively. Ninety-five percent of the SFRT patients received TMZ versus 100% of those treated with HRT. Patients receiving HRT were older (median, 72 vs 66 years). All HRT patients were treated with the intensity modulated radiation therapy (IMRT) technique versus SFRT, in which 57% had IMRT. Multivariate Cox regression showed decreased overall survival (OS) associated with patient age >70 (hazard ratio [HR], 1.84), lower Karnofsky performance status (HR, 5.25), biopsy versus surgical resection (HR, 4.18), radiation therapy planning technique 3- or 2-dimensional planning versus IMRT (HR, 1.91; HR, 3.40, respectively). Analysis restricted to patients receiving IMRT-based planning showed no difference in OS between HRT and SFRT. For patients receiving TMZ, there was no survival difference between those treated with HRT and those treated with SFRT. CONCLUSIONS Elderly GBM patients receiving HRT and those receiving SFRT had similar OS. Subset analysis patients receiving concurrent TMZ showed no difference in OS between the HRT and SFRT groups.

Radiation-Induced Dermatitis is Mediated by IL17-Expressing γδ T Cells

Radiation dermatitis is a serious cutaneous injury caused by radiation therapy or upon accidental nuclear exposure. However, the pathogenic immune mechanisms underlying this injury are still poorly understood. We seek to discover how the dysregulated immune response after irradiation orchestrates skin inflammation. The skin on the left flank of C57BL/6J wild-type and C57BL/6J Tcrd–/– mice, which are deficit in γδ T cells, was exposed to a single X-ray dose of 25 Gy, and the right-flank skin was used as a sham-irradiated control. At 4 weeks postirradiation, the wild-type skin exhibited signs of depilation, erythema and desquamation. Histological analysis showed hyperproliferation of keratinocytes and acanthosis. Dramatic elevation of IL17-expressing T cells was identified from the irradiated skin, which was mainly contributed by γδ T cells and innate lymphoid cells, rather than Th17 cells. Furthermore, protein levels of critical cytokines for IL17-expressing γδ T cell activation, IL1β and IL23 were found markedly upregulated. Lastly, radiation-induced dermatitis was significantly attenuated in γδ T cell knockout mice. In vitro, normal human epidermal keratinocytes (NHEKs) could be initiator cells of inflammation by providing a great number of pro-inflammatory mediators upon radiation, and as well as effector cells of epidermal hyperplasia in response to exogenous IL17 and/or IL22 treatment. Our findings implicate a novel role of IL17-expressing γδ T cells in mediating radiation-induced skin inflammation. This study reveals the innate immune response pathway as a potential therapeutic target for radiation skin injury.

Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development

Breast cancer brain metastasis (BCBM) is associated with high morbidity and mortality. Patients with breast cancer risk factors associated with rapid development of BCBM could potentially benefit from early brain metastasis screening. We retrospectively reviewed all BCBM patients treated with brain radiotherapy at our institution from 1997 to 2015. Interval time to BCBM was defined as date of pathologic breast cancer diagnosis to date of radiographic evidence of brain metastasis. Patients were stratified by breast cancer molecular subtype and stage at diagnosis. Kaplan Meier analysis was conducted on time to development of BCBM. Breast cancer risk factors were correlated with time to BCBM on Cox proportion hazard analysis. The study cohort comprised 121 BCBM patients, with median interval time to BCBM of 46 months. Times to BCBM for Her2+/2HR+, Her2+, Her2−/HR+, and triple-negative (TNBC) subtypes were 70, 44, 42, and 28 months respectively (p = 0.002). Time to BCBM for stages I, II, III, and IV were 70, 54, 29, and 24 months, respectively (p = 0.000). BCBM patients were further stratified by both molecular subtype (TNBC vs. non-TNBC) and stage (I, II vs. III, IV). Median times to BCBM for non-TNBC/stage I–II, TNBC/stage I–II, non-TNBC stage III–IV, and TNBC/stage III–IV were 68, 47, 29, and 6 months respectively (p = 0.000). Subtype and stage were associated with shorter time to BCBM on multivariate analysis. Subtype and initial stage are independently correlated with decreased time to development of BCBM. Patients with advanced high stage and triple negative breast cancer develop brain metastases significantly earlier.