Christina Tsien

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer

PURPOSE To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer: Response and Survival Positively Associated With HPV16 Copy Number

PURPOSE To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. PATIENTS AND METHODS Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. RESULTS Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). CONCLUSION Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival.

PURPOSE Assessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival. PATIENTS AND METHODS Sixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival. RESULTS Greater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome. CONCLUSION Compared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

The parametric response map is an imaging biomarker for early cancer treatment outcome

Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.

Parametric Response Map As an Imaging Biomarker to Distinguish Progression From Pseudoprogression in High-Grade Glioma

PURPOSE To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma. PATIENTS AND METHODS Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board-approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. RESULTS Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRM(rCBV)) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression. CONCLUSION PRM(rCBV) at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.

Ipilimumab and radiation therapy for melanoma brain metastases

Ipilimumab, an antibody that enhances T‐cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy. We hypothesized that patients with melanoma brain metastasis treated with both ipilimumab and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain. We analyzed the clinical and radiographic records of melanoma patients with brain metastases who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. The hazard ratios for survival were estimated to assess outcomes as a function of ipilimumab use and radiation type. Seventy patients were identified, 33 of whom received ipilimumab and 37 who did not. The patients who received ipilimumab had a censored median survival of 18.3 months (95% confidence interval 8.1–25.5), compared with 5.3 months (95% confidence interval 4.0–7.6) for patients who did not receive ipilimumab. Ipilimumab and stereotactic radiosurgery were each significant predictors of improved overall survival (hazard ratio = 0.43 and 0.45, with P = 0.005 and 0.008, respectively). Four of 10 evaluable patients (40.0%) who received ipilimumab prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not receive ipilimumab. Ipilimumab is associated with a significantly reduced risk of death in patients with melanoma brain metastases who underwent radiotherapy, and this finding supports the need for multimodality therapy to optimize patient outcomes. Prospective studies are needed and are underway.

The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas.

OBJECTIVE:Radiotherapy after aggressive surgical resection of nonfunctional macroadenoma (NFA) of the pituitary remains controversial. Historically, immediate postoperative radiotherapy has been recommended to decrease risk of recurrence. With the availability of high-resolution imaging, most neurosurgeons now withhold radiation until recurrence. There is relatively little evidence to support this practice, however. This study reviews postoperative results in a large number of patients with NFA, the majority of whom did not undergo prophylactic radiation. METHODS:Of the 258 patients who underwent surgery from 1979 to 1999 for NFA, medical records were available for 176. Forty-four patients were treated with immediate postoperative radiotherapy after tumor resection, and the remaining 132 patients were followed up with serial imaging studies and treated with radiotherapy only when a recurrence was documented by follow-up imaging. RESULTS:Patients in the group that received immediate postoperative radiotherapy at time of initial diagnosis and surgery did not differ significantly with respect to age or sex from those in the group that was observed. Five- and 10-year recurrence rates were 2.3 and 2.3%, respectively, for patients who received immediate postoperative radiotherapy, as compared with 15.2 and 50.5%, respectively, for patients who were followed up and did not receive radiotherapy unless there was evidence of recurrence or progression. No patient had symptomatic recurrence in the group that was observed if consistent follow-up was performed. Of the 26 patients who received radiotherapy at time of tumor recurrence or progression, 18 had adequate follow-up, and in all cases, the tumors either remained stable or regressed. CONCLUSION:Withholding radiotherapy after a high-percentage resection of NFA leads to a higher recurrence rate, but it avoids exposing all patients to the risks of radiation. Deferring radiotherapy for patients with complete or near-complete resection seems to be a safe and prudent approach, as our data suggest that recurrences may be detected early with high-resolution imaging and treated effectively with radiation at time of recurrence. Therefore, immediate postoperative radiotherapy may be eliminated for patients with complete or near complete resection of NFA and who agree to undergo close follow-up for a long period.

Use of Magnetic Resonance Imaging to Assess Blood-Brain/Blood-Glioma Barrier Opening During Conformal Radiotherapy

PURPOSE For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas. PATIENTS AND METHODS Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received. RESULTS In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation. CONCLUSION Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.

Radiation-Induced Changes in Normal-Appearing White Matter in Patients With Cerebral Tumors: A Diffusion Tensor Imaging Study

PURPOSE To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients. METHODS AND MATERIALS Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (), fractional anisotropy of diffusion, diffusivity perpendicular (lambdaperpendicular) and parallel (lambda||) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum. RESULTS In the genu and splenium, fractional anisotropy decreased and , lambda||, lambdaperpendicular increased linearly and significantly with time (p<0.01). At 45 weeks after the start of RT, lambdaperpendicular had increased approximately 30% in the genu and splenium, and lambda|| had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in lambdaperpendicular and lambda|| were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in lambdaperpendicular and lambda|| was not sustained after 32 weeks, indicating the transition from focal to diffuse effects. CONCLUSION The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.