James B. Yu

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING Merck and the Yale Cancer Center.

Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival

OBJECT A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival. METHODS The authors conducted an institutional review board-approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated. RESULTS Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03). CONCLUSIONS The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4-6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.

A retrospective review of 1349 cases of sebaceous carcinoma.

Sebaceous carcinoma is a rare and aggressive cutaneous carcinoma. It is believed that this malignancy predominates in the periocular region and occurs more frequently in Asian populations and in women. The objective of the current study was to analyze demographic characteristics and outcomes for patients with this malignancy from a large United States‐based population registry.

Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation

This study assessed the cumulative incidence of clinically significant cardiac disease in 1279 Hodgkin lymphoma patients treated with mediastinal irradiation and quantified the standard incidence ratios (SIRs) and absolute excess risks of cardiac procedures compared with a normal matched population. Cox regression analysis was used to explore factors associated with cardiac complications. Poisson regression analysis of SIRs was used to estimate the excess risk of cardiac interventions from mediastinal irradiation. After a median follow-up of 14.7 years, 187 patients experienced 636 cardiac events and 89 patients required a cardiac procedure. 5-, 10-, 15-, and 20-year cumulative incidence rates of cardiac events were 2.2%, 4.5%, 9.6%, and 16%. SIRs for cardiac procedures were increased for coronary artery bypass graft (3.19), percutaneous intervention (1.55), implantable cardioverter defibrillator or pacemaker placement (1.9), valve surgery (9.19), and pericardial surgery (12.91). Absolute excess risks were 18.2, 19.3, 9.4, 14.1, and 4.7 per 10 000 person-years, respectively. Older age at diagnosis and male sex were predictors for cardiac events. However, younger age at diagnosis was associated with excess risk specifically from radiation therapy compared with the general population. These results may help guideline development for both the types and timing of cardiac surveillance in survivors of Hodgkin lymphoma.

Immortal time bias: a frequently unrecognized threat to validity in the evaluation of postoperative radiotherapy.

PURPOSE To evaluate the influence of immortal time bias on observational cohort studies of postoperative radiotherapy (PORT) and the effectiveness of sequential landmark analysis to account for this bias. METHODS AND MATERIALS First, we reviewed previous studies of the Surveillance, Epidemiology, and End Results (SEER) database to determine how frequently this bias was considered. Second, we used SEER to select three tumor types (glioblastoma multiforme, Stage IA-IVM0 gastric adenocarcinoma, and Stage II-III rectal carcinoma) for which prospective trials demonstrated an improvement in survival associated with PORT. For each tumor type, we calculated conditional survivals and adjusted hazard ratios of PORT vs. postoperative observation cohorts while restricting the sample at sequential monthly landmarks. RESULTS Sixty-two percent of previous SEER publications evaluating PORT failed to use a landmark analysis. As expected, delivery of PORT for all three tumor types was associated with improved survival, with the largest associated benefit favoring PORT when all patients were included regardless of survival. Preselecting a cohort with a longer minimum survival sequentially diminished the apparent benefit of PORT. CONCLUSIONS Although the majority of previous SEER articles do not correct for it, immortal time bias leads to altered estimates of PORT effectiveness, which are very sensitive to landmark selection. We suggest the routine use of sequential landmark analysis to account for this bias.

Re: Proton vs Intensity-Modulated Radiotherapy for Prostate Cancer: Patterns of Care and Early Toxicity

Over the past decade, intensity modulated radiotherapy (IMRT) has become the standard form of radiotherapy for the treatment of prostate cancer, accounting for more than 80% of all radiotherapy (1). Even as IMRT has been widely adopted, other radiotherapy modalities have come to market, most notably proton radiotherapy (PRT). Although PRT predates IMRT, dissemination of PRT has been increasing rapidly in recent years. In part because of its high capital cost, Medicare is reported to reimburse PRT at a rate 1.4 to 2.5 times that of IMRT (2–4), despite many unexplored questions. First, there is a lack of data regarding national patterns of use and the true cost of PRT among Medicare beneficiaries. Currently, there are only nine PRT centers in operation in the United States (5), and this relatively low treatment capacity limits costs. However, eight other centers are in development (5), along with smaller and more affordable proton machines (6), conceivably opening the door to more widespread adoption of PRT across the country. Second, the Institute for Clinical and Economic Review concluded unanimously that the state of current knowledge of comparative clinical effectiveness was “insufficient” (7,8). Because differences in cancer cure rates and survival from prostate cancer treatment often take many years to become evident, it has been suggested that initial study of prostate cancer treatments should focus on treatment-related toxicity (8). Proponents of PRT argue that the physical properties of protons may decrease the most common side effects associated with prostate radiotherapy—gastrointestinal and genitourinary toxicity (9). Early outcomes from single-arm, prospective trials investigating PRT are forthcoming, indicating low levels of radiation-induced toxicity with early follow-up (10,11). However, IMRT itself has a robust literature describing excellent efficacy and low toxicity in the treatment of prostate cancer (12). Therefore, it is unclear that PRT offers a statistically significant benefit beyond IMRT. Prior studies investigating PRT in Medicare beneficiaries using the Surveillance, Epidemiology, and End Results–Medicare database have been single-institution studies (13,14) and, therefore, are not of the whole country. These studies (13,14) noted a statistically significant reduction of gastrointestinal toxicity for patients undergoing IMRT compared with PRT. A comprehensive comparison of PRT with IMRT requires examination of the entire country for the most recent years available. As more PRT centers become operational, it will be crucial for patients, providers, and policy makers to understand the cost and national pattern of adoption of PRT and the incidence of treatment-related toxicity compared with IMRT. Therefore, we used a national sample of Medicare beneficiaries with prostate cancer to investigate the patterns and cost of PRT delivery, as well as the early treatment-related toxicity associated with PRT compared with IMRT.

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis

PURPOSE We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis. PATIENTS AND METHODS A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. RESULTS Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). CONCLUSION Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.

Stereotactic Body Radiation Therapy Versus Intensity-Modulated Radiation Therapy for Prostate Cancer: Comparison of Toxicity

PURPOSE Stereotactic body radiation therapy (SBRT) is a technically demanding prostate cancer treatment that may be less expensive than intensity-modulated radiation therapy (IMRT). Because SBRT may deliver a greater biologic dose of radiation than IMRT, toxicity could be increased. Studies comparing treatment cost to the Medicare program and toxicity are needed. METHODS We performed a retrospective study by using a national sample of Medicare beneficiaries age ≥ 66 years who received SBRT or IMRT as primary treatment for prostate cancer from 2008 to 2011. Each SBRT patient was matched to two IMRT patients with similar follow-up (6, 12, or 24 months). We calculated the cost of radiation therapy treatment to the Medicare program and toxicity as measured by Medicare claims; we used a random effects model to compare genitourinary (GU), GI, and other toxicity between matched patients. RESULTS The study sample consisted of 1,335 SBRT patients matched to 2,670 IMRT patients. The mean treatment cost was

Assessing the Impact of a Cooperative Group Trial on Breast Cancer Care in the Medicare Population

13,645 for SBRT versus

Surveillance Epidemiology and End Results Evaluation of the Role of Surgery for Stage I Small Cell Lung Cancer

21,023 for IMRT. In the 6 months after treatment initiation, 15.6% of SBRT versus 12.6% of IMRT patients experienced GU toxicity (odds ratio [OR], 1.29; 95% CI, 1.05 to 1.53; P = .009). At 24 months after treatment initiation, 43.9% of SBRT versus 36.3% of IMRT patients had GU toxicity (OR, 1.38; 95% CI, 1.12 to 1.63; P = .001). The increase in GU toxicity was due to claims indicative of urethritis, urinary incontinence, and/or obstruction. CONCLUSION Although SBRT was associated with lower treatment costs, there appears to be a greater rate of GU toxicity for patients undergoing SBRT compared with IMRT, and prospective correlation with randomized trials is needed.