T.J.C. Wang

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.

An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825

Background Glioblastoma (GBM) is the most common primary malignant brain tumor. Nomograms are often used for individualized estimation of prognosis. This study aimed to build and independently validate a nomogram to estimate individualized survival probabilities for patients with newly diagnosed GBM, using data from 2 independent NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials. Methods This analysis included information on 799 (RTOG 0525) and 555 (RTOG 0825) eligible and randomized patients with newly diagnosed GBM and contained the following variables: age at diagnosis, race, gender, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, and survival (in months). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the 0525 data and were independently validated using the 0825 data. Models were internally validated using 10-fold cross-validation, and individually predicted 6-, 12-, and 24-month survival probabilities were generated to measure the predictive accuracy and calibration against the actual survival status. Results A final nomogram was built using the Cox proportional hazards model. Factors that increased the probability of shorter survival included greater age at diagnosis, male gender, lower KPS, not having total resection, and unmethylated MGMT status. Conclusions A nomogram that assesses individualized survival probabilities (6-, 12-, and 24-mo) for patients with newly diagnosed GBM could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: http://cancer4.case.edu/rCalculator/rCalculator.html.

Neurocognitive Deficits after Radiation Therapy for Brain Malignancies

Radiotherapy (RT) has proven to be an effective therapeutic tool in treatment of a wide variety of brain tumors; however, it has a negative impact on quality of life and neurocognitive function. Cognitive dysfunction associated with both the disease and adverse effects of RT is one of the most concerning complication among long-term survivors. The effects of RT to brain can be divided into acute, early delayed, and late delayed. It is, however, the late delayed effects of RT that lead to severe neurological consequences such as minor-to-severe cognitive deficits due to irreversible focal or diffuse necrosis of brain parenchyma. In this review, we discuss current and emerging data regarding the relationship between RT and neurocognitive outcomes, and therapeutic strategies to prevent/treat postradiation neurocognitive deficits.

Quantitative ultrasonic evaluation of radiation-induced late tissue toxicity: pilot study of breast cancer radiotherapy.

PURPOSE To investigate the use of advanced ultrasonic imaging to quantitatively evaluate normal-tissue toxicity in breast-cancer radiation treatment. METHODS AND MATERIALS Eighteen breast cancer patients who received radiation treatment were enrolled in an institutional review board-approved clinical study. Radiotherapy involved a radiation dose of 50.0 to 50.4 Gy delivered to the entire breast, followed by an electron boost of 10.0 to 16.0 Gy delivered to the tumor bed. Patients underwent scanning with ultrasound during follow-up, which ranged from 6 to 94 months (median, 22 months) postradiotherapy. Conventional ultrasound images and radio-frequency (RF) echo signals were acquired from treated and untreated breasts. Three ultrasound parameters, namely, skin thickness, Pearson coefficient, and spectral midband fit, were computed from RF signals to measure radiation-induced changes in dermis, hypodermis, and subcutaneous tissue, respectively. Ultrasound parameter values of the treated breast were compared with those of the untreated breast. Ultrasound findings were compared with clinical assessment using Radiation Therapy Oncology Group (RTOG) late-toxicity scores. RESULTS Significant changes were observed in ultrasonic parameter values of the treated vs. untreated breasts. Average skin thickness increased by 27.3%, from 2.05 ± 0.22 mm to 2.61 ± 0.52 mm; Pearson coefficient decreased by 31.7%, from 0.41 ± 0.07 to 0.28 ± 0.05; and midband fit increased by 94.6%, from -0.92 ± 7.35 dB to 0.87 ± 6.70 dB. Ultrasound evaluations were consistent with RTOG scores. CONCLUSIONS Quantitative ultrasound provides a noninvasive, objective means of assessing radiation-induced changes to the skin and subcutaneous tissue. This imaging tool will become increasingly valuable as we continue to improve radiation therapy technique.

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.

Management of Borderline Resectable Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma is the fourth most common cause of cancer-related death among U.S. men and women. Despite much effort in translational research, pancreatic adenocarcinoma remains a challenging disease with an overall 5-year survival rate less than 5%. To date, the only potentially curative treatment for managing pancreatic adenocarcinoma is surgical resection. However, more than 80% of patients are deemed either unresectable or metastatic upon diagnosis. For borderline resectable disease, although there is no high-level evidence supporting its use, an initial approach involving neoadjuvant therapy is preferred, as opposed to immediate surgery. In this years ASCO Gastrointestinal Cancers Symposium, several studies were presented with approaches towards treating borderline resectable pancreatic adenocarcinoma. Retrospective studies (Abstract #280, #304, #327) were presented and showed that neoadjuvant chemoradiation were associated with higher rates of negative margin resection and better survival. The tolerability of accelerated fraction radiotherapy with concomitant capecitabine was demonstrated in a phase I study (Abstract #329). More effective therapeutic approaches and prospective studies are needed for this devastating illness. This highlight article will focus on the management of borderline resectable pancreatic adenocarcinoma.

Radiation Therapy for the Management of Brain Metastases.

Brain metastases are the most common malignant intracranial tumors and carry a poor prognosis. The management of brain metastases may include a variety of treatment modalities including surgical resection, radiation therapy, and/or systemic therapy. The traditional treatment for brain metastasis involved whole brain irradiation. However, improved systemic control of primary cancers has led to longer survival for some groups of patients and there is increasing need to consider the late effects of radiation to the entire brain. With advances in imaging and radiation treatment planning and delivery stereotactic radiosurgery has become more frequently utilized and may be delivered through Gamma Knife Stereotactic Radiosurgery or linear accelerator-based systems. Furthermore, experience in treating thousands of patients on clinical trials has led to diagnosis-specific prognostic assessment systems that help guide our approach to the management of this common clinical scenario. This review provides an overview of the literature supporting radiotherapy for brain metastasis and an update on current radiotherapeutic options that is tailored for the nonradiation oncologist.

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.

Efficacy and outcomes of facial nerve–sparing treatment approach to cerebellopontine angle meningiomas

OBJECTIVE Advanced microsurgical techniques contribute to reduced morbidity and improved surgical management of meningiomas arising within the cerebellopontine angle (CPA). However, the goal of surgery has evolved to preserve the quality of the patients life, even if it means leaving residual tumor. Concurrently, Gamma Knife radiosurgery (GKRS) has become an acceptable and effective treatment modality for newly diagnosed, recurrent, or progressive meningiomas of the CPA. The authors review their institutional experience with CPA meningiomas treated with GKRS, surgery, or a combination of surgery and GKRS. They specifically focus on rates of facial nerve preservation and characterize specific anatomical features of tumor location with respect to the internal auditory canal (IAC). METHODS Medical records of 76 patients with radiographic evidence or a postoperative diagnosis of CPA meningioma, treated by a single surgeon between 1992 and 2016, were retrospectively reviewed. Patients with CPA meningiomas smaller than 2.5 cm in greatest dimension were treated with GKRS, while patients with tumors 2.5 cm or larger underwent facial nerve-sparing microsurgical resection where appropriate. Various patient, clinical, and tumor data were gathered. Anatomical features of the tumor origin as seen on preoperative imaging confirmed by intraoperative investigation were evaluated for prognostic significance. Facial nerve preservation rates were evaluated. RESULTS According to our treatment paradigm, 51 (67.1%) patients underwent microsurgical resection and 25 (32.9%) patients underwent GKRS. Gross-total resection (GTR) was achieved in 34 (66.7%) patients, and subtotal resection (STR) in 17 (33.3%) patients. Tumors recurred in 12 (23.5%) patients initially treated surgically, requiring additional surgery and/or GKRS. Facial nerve function was unchanged or improved in 68 (89.5%) patients. Worsening facial nerve function occurred in 8 (10.5%) patients, all of whom had undergone microsurgical resection. Upfront treatment with GKRS for CPA meningiomas smaller than 2.5 cm was associated with preservation of facial nerve function in all patients over a median follow-up of 46 months, regardless of IAC invasion and tumor origin. Anatomical origin was associated with extent of resection but did not correlate with postoperative facial nerve function. Tumor size, extent of resection, and the presence of an arachnoid plane separating the tumor and the contents of the IAC were associated with postoperative facial nerve outcomes. CONCLUSIONS CPA meningiomas remain challenging lesions to treat, given their proximity to critical neurovascular structures. GKRS is a safe and effective option for managing CPA meningiomas smaller than 2.5 cm without associated mass effect or acute neurological symptoms. Maximal safe resection with preservation of neurological function can be performed for tumors 2.5 cm or larger without significant risk of facial nerve dysfunction, and, when combined with GKRS for recurrence and/or progression, provides excellent disease control. Anatomical features of the tumor origin offer critical insights for optimizing facial nerve preservation in this cohort.