Eric Ojerholm

Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis

OBJECT Following resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy. METHODS A retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. RESULTS Common primary tumors were non-small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm(3). Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter ≥ 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively). CONCLUSIONS This study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy.

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710

Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil‐to‐lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC).

Gamma Knife radiosurgery to four or more brain metastases in patients without prior intracranial radiation or surgery

Data on stereotactic radiosurgery (SRS) for four or more metastases are limited. Existing studies are confounded by significant proportions of patients receiving prior whole‐brain radiation therapy (WBRT) or concurrent WBRT with SRS. Furthermore, published results disagree about the impact of tumor volume on overall survival. A retrospective review identified 38 patients without prior intracranial radiation or surgery who received Gamma Knife (GK) as sole treatment to ≥4 brain metastases in a single session. Twenty‐eight cases with follow‐up imaging were analyzed for intracranial progression. Prognostic factors were examined by univariate (log‐rank test) and multivariate (Cox proportional hazards model) analyses. Common primary tumors were non‐small cell lung (45%), melanoma (37%), and breast (8%). Cases were recursive partitioning analysis class II (94%) or III (6%). Patients harbored a median five tumors (range 4–12) with median total tumor volume of 1.2 cc. A median dose of 21 Gy was prescribed to the 50% isodose line. Patients survived a median 6.7 months from GK. Local treatment failure occurred in one case (4%) and distant failure in 22 (79%). On multivariate analysis, total tumor volume ≥3 cc was significantly associated with distant failure and worsened overall survival (P = 0.042 and 0.040). Fourteen patients (37%) underwent salvage WBRT at a median 10.3 months from GK and seven patients received repeat GK. GK as sole initial treatment for four or more simultaneous metastases spares some patients WBRT and delays it for others. Increased total tumor volume (≥3 cc) is significantly associated with worsened overall survival.

Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy

Abstract Background. Concurrent chemoradiotherapy cures most patients with anal squamous cell carcinoma at the cost of significant treatment-related toxicities. Intensity-modulated radiotherapy (IMRT) reduces side effects compared to older techniques, but whether proton beam therapy (PBT) offers additional advantages is unclear. Material and methods. Eight patients treated with PBT for anal cancer were chosen for this study. We conducted detailed plan comparisons between pencil-beam scanning PBT via two posterior oblique fields and seven-field IMRT. Cumulative dose-volume histograms were analyzed by Wilcoxon signed-rank test, and plan delivery robustness was assessed via verification computed tomography (CT) scans obtained during treatment. Results. Compared to IMRT, PBT reduced low dose radiation (≤ 30 Gy) to the small bowel, total pelvic bone marrow, external genitalia, femoral heads, and bladder (all p < 0.05) without compromising target coverage. For PBT versus IMRT, mean small bowel volume receiving ≥ 15 Gy (V15) was 81 versus 151 cm3, mean external genitalia V20 was 14 versus 40%, and mean total pelvic bone marrow V15 was 66 versus 83% (all p = 0.008). The lumbosacral bone marrow dose was higher with PBT due to beam geometry. PBT was delivered with ≤ 1.3% interfraction deviation in the dose received by 98% of the clinical target volumes. Conclusion. Pencil-beam scanning PBT is clinically feasible and can be robustly delivered for anal cancer patients. Compared with IMRT, PBT reduces low dose radiation to important organs at risk in this population. While the clinical benefit of these differences remains to be shown, existing data suggest that limiting low dose to the small bowel and pelvic bone marrow may reduce treatment toxicity.

Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer

PURPOSE Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. METHODS AND MATERIALS The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network--recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. RESULTS Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non-academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. CONCLUSIONS Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered.

Stereotactic radiosurgery alone for small cell lung cancer: a neurocognitive benefit?

Yomo and Hayashi reported results of stereotactic radiosurgery alone for brainmetastases from small cell lung cancer. This strategy aims to avoid theneurocognitive effects of whole-brain radiation therapy. However, radiosurgeryalone increases the risk of distant intracranial relapse, which canindependently worsen cognition. This concern is heightened in histologies likesmall cell with high predilection for intracranial spread. The majority of studypatients developed new brain disease, suggesting radiosurgery alone may not bean optimal strategy for preserving neurocognitive function in this population.We suggest whole-brain radiation therapy should remain the standard of care forsmall cell lung cancer.

Reply to comment on: Insurance coverage decisions for pediatric proton therapy

To the Editor: Dr. Schefft raises several important points.1 First, proton beam therapy (PBT) has potential benefits, but level 1 evidence to support its use does not exist. Second, the cost of these expensive treatments is partially shouldered by patients and families. Third, highquality comparative data are needed. We agree. In particular, strong comparative evidence will help us recommend the right treatment for the right patient in the context of finite resources.2,3 We are hopeful that ongoing studies will clarify the role of PBT for pediatric cancers.4 Until that time, however, we remain in an evidentiary gray zone. Our studys goal was to examine insurance policies and practices in this situation.5 Wediscoveredunfavorablepolicy languageandupfront denials—but in the end, nearly every case was approved.5 We highlighted time and resources that appear to be wasted for all involved parties, suggesting that improvements could be made to the status quo. We are not alone in calling for a streamlined review process. For example, theAmericanSociety ofClinicalOncology recentlymade similar recommendations regarding insurance authorization for expensive cancer drugs.6 Of course, no coveragepolicy is etched in stone. Payerswill adjust as new evidence about PBT emerges. For now, however, it may be worth reconciling policy languagewith real-world practice. Finally, Dr. Schefft poses a question: until conclusive evidence emerges, should patients be referred for PBT? National organizations can provide some guidance; for example, the American Society for Radiation Oncology recently issued an updated PBT model policy.7 In our view, the primary responsibility rests with individual institutions and practitioners. The oncology team must thoughtfully select appropriate patients. For example, all of our cases are screened by a team of clinical experts; we do not request coverage for most palliative cases or other inappropriate indications. We are hopeful that other institutions will also use deliberate selection methods. Together, we can provide high-quality care for our patients while respecting the costs and burdens of advanced technologies. Eric Ojerholm1,2,3 Christine E. Hill-Kayser1 1Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 2Department of Radiation Oncology, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania 3Senior Fellow, Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania Correspondence Eric Ojerholm, Department of Radiation Oncology, University of Pennsylvania, 3400 Civic Center Boulevard, PCAM-2West, Philadelphia, PA 19104. Email: eric.ojerholm@uphs.upenn.edu

Initiative to reduce bone scans for low-risk prostate cancer patients: A quasi-experimental before-and-after study in a Veterans Affairs hospital

Purpose Bone scans (BS) are a low-value test for asymptomatic men with low-risk prostate cancer. We performed a quality improvement intervention aimed at reducing BS for these patients. Methods and materials The intervention was a presentation that leveraged the behavioral science concepts of social comparison and normative appeals. Participants were multidisciplinary stakeholders from the Radiation Oncology and Urology services at a Veterans Affairs hospital. We determined the baseline rate of BS by retrospectively analyzing cases of asymptomatic men with newly diagnosed low-risk prostate cancer. For social comparison, we presented contemporary peer BS rates in the United States—including Veterans Affairs hospitals. For normative appeals, we reviewed guidelines from various professional groups. To analyze the effect of this intervention, we performed a quasi-experimental, uncontrolled, before-and-after study. Results During the 1-year period before the intervention, 32 of 37 patients with low-risk prostate cancer (86.5%) received a BS. The contemporary peer rate was approximately 30%. All reviewed guidelines recommended against BS. During the 1-year period after the intervention, the rate of BS was reduced to 65.5% (19 of 29 patients; P = .043 by one-sided Fishers exact test). Conclusions We observed a modest reduction in guideline-discordant BS after the quality improvement intervention. BS rates might be influenced by initiatives that combine social comparisons with appeals to professional norms.

Insurance coverage decisions for pediatric proton therapy

Proton beam therapy (PBT) holds promise for pediatric patients, but level 1 evidence is not available. In this context, we examined insurance coverage decisions at our facility from 2010 to 2015. PBT was initially denied for 11% of pediatric cases. However, nearly all denials were overturned on appeal—a process that often delayed care by more than a week. Despite unfavorable language in coverage policies, real‐world decisions were eventual approval in >99% of cases. Payers appear to have largely accepted the current level‐of‐evidence for pediatric PBT, but all parties spend significant time and resources on appeals. Streamlined approval processes could align incentives among stakeholders.

Reply to Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710: Reply to Correspondence

In their letter, Dolan and McMillan raise several important points. First, many studies have concluded that the neutrophil-to-lymphocyte ratio (NLR) is a cancer biomarker. Second, the majority of studies analyzed NLR as a dichotomized variable. In contrast, we kept NLR in its continuous form; our study found no evidence that NLR is prognostic or predictive of survival in patients with muscle-invasive bladder cancer. Guidelines recommend analyzing variables in their continuous form. The statistical shortcomings of dichotomization, including the risk of spurious findings, have been shown elsewhere in detail. Furthermore, a continuous variable can be split at many different cutpoints; this inflates researcher degrees of freedom and may raise issues of multiple comparisons. We appreciate the opportunity to highlight these concerns regarding the existing NLR literature. Therefore, our study kept NLR as a continuous variable. Analytic checks supported the modeling assumptions of this approach (eg, a linear functional relationship and proportional hazards). However, for the sake of transparency, we present here the results using dichotomized NLR at the thresholds of 3 and 5, as per the request of Dolan and McMillan. In multivariable models adjusted for age, sex, tumor T category, and treatment arm, NLR was neither prognostic for overall survival (hazard ratio [HR], 1.32 [95% confidence interval (95% CI), 0.97-1.79; P 5.07] for a cutpoint 3 and HR, 1.17 [95% CI, 0.76-1.81; P 5.46] for a cutpoint 5) nor predictive of the benefit from neoadjuvant chemotherapy (HR, 0.97 [95% CI, 0.56-1.70; P 5.92] for a cutpoint 3 and HR, 0.63 [95% CI, 0.291.38; P 5.25] for a cutpoint 5). We note that, in this case, the threshold for statistical significance would be below the traditional level of .05 due to multiple comparisons. In short, the dichotomized results do not change our study’s conclusions. FUNDING SUPPORT No specific funding was disclosed.