Nils D. Arvold

Age, Breast Cancer Subtype Approximation, and Local Recurrence After Breast-Conserving Therapy

PURPOSE Prior results of breast-conserving therapy (BCT) have shown substantial rates of local recurrence (LR) in young patients with breast cancer (BC). PATIENTS AND METHODS We studied 1,434 consecutive patients with invasive BC who received BCT from December 1997 to July 2006. Ninety-one percent received adjuvant systemic therapy; no patients received trastuzumab. Five BC subtypes were approximated: estrogen receptor (ER) or progesterone receptor (PR) positive, HER2 negative, and grades 1 to 2 (ie, luminal A); ER positive or PR positive, HER2 negative, and grade 3 (ie, luminal B); ER or PR positive, and HER2 positive (ie, luminal HER2); ER negative, PR negative, and HER2 positive (ie, HER2); and ER negative, PR negative, and HER2 negative (ie, triple negative). Actuarial rates of LR were calculated by using the Kaplan-Meier method. RESULTS Median follow-up was 85 months. Overall 5-year cumulative incidence of LR was 2.1% (95% CI, 1.4% to 3.0%). The 5-year cumulative incidence of LR was 5.0% (95% CI, 3.0% to 8.3%) for age quartile 23 to 46 years; 2.2% (95% CI, 1.0% to 4.6%) for ages 47 to 54 years; 0.9% (95% CI, 0.3% to 2.6%) for ages 55 to 63 years; and 0.6% (95% CI, 0.1% to 2.2%) for ages 64 to 88 years. The 5-year cumulative incidence of LR was 0.8% (95% CI, 0.4% to 1.8%) for luminal A; 2.3% (95% CI, 0.8% to 5.9%) for luminal B; 1.1% (95% CI, 0.2% 7.4%) for luminal HER2; 10.8% (95% CI, 4.6% to 24.4%) for HER2; and 6.7% (95% CI, 3.6% to 12.2%) for triple negative. On multivariable analysis, increasing age was associated with decreased risk of LR (adjusted hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = .009). CONCLUSION In the era of systemic therapy and BC subtyping, age remains an independent prognostic factor after BCT. However, the risk of LR for young women appears acceptably low.

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.

PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas

The phosphoinositide 3-kinase (PI3-kinase) signaling pathway is frequently aberrantly activated in glioblastoma multiforme (GM) by mutation or loss of the 3′ phospholipid phosphatase PTEN. PTEN abnormalities result in inappropriate signaling to downstream molecules including protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). PI3-kinase activation increases resistance to radiation-induced cell death; conversely, PI3-kinase inhibition enhances the sensitivity of tumors to radiation. The effects of LY294002, a biochemical inhibitor of PI3-kinase, on the response to radiation were examined in the PTEN mutant glioma cell line U251 MG. Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation. In contrast to LY294002, rapamycin, an inhibitor of mTOR, did not result in radiosensitization. We demonstrate that among multiple known targets of LY294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization. Furthermore, using a myristoylated PKB/Akt construct, we identified PKB/Akt as the downstream molecule that mediates the synergistic cytotoxicity between LY294002 and radiation. Thus PI3-kinase dysregulation may contribute to the notable radioresistance of GM tumors and inhibition of PKB/Akt offers an excellent target to enhance radiosensitivity.

Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA).

Importance Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. As systemic therapies improve, patients with lung cancer live longer and thus are at increased risk for brain metastases. Understanding how prognosis varies across this heterogeneous patient population is essential to individualize care and design future clinical trials. Objective To update the current Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non–small-cell lung cancer (NSCLC) and brain metastases. The DS-GPA is based on data from patients diagnosed between 1985 and 2005, and we set out to update it by incorporating more recently reported gene and molecular alteration data for patients with NSCLC and brain metastases. This new index is called the Lung-molGPA. Design, Setting, and Participants This is a multi-institutional retrospective database analysis of 2186 patients diagnosed between 2006 and 2014 with NSCLC and newly diagnosed brain metastases. The multivariable analyses took place between December 2015 and May 2016, and all prognostic factors were weighted for significance by hazard ratios. Significant factors were included in the updated Lung-molGPA prognostic index. Main Outcomes and Measures The main outcome was survival. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. Log rank tests were used to compare adjacent classes and to compare overall survival for adenocarcinoma vs nonadenocarcinoma groups. Results The original DS-GPA was based on 4 factors found in 1833 patients with NSCLC and brain metastases diagnosed between 1985 and 2005: patient age, Karnofsky Performance Status, extracranial metastases, and number of brain metastases. The patients studied for the creation of the DS-GPA had a median survival of 7 months from the time of initial treatment of brain metastases. To design the updated Lung-molGPA, we analyzed data from 2186 patients from 2006 through 2014 with NSCLC and newly diagnosed brain metastases (1521 adenocarcinoma and 665 nonadenocarcinoma). Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma). The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years. Conclusions and Relevance In recent years, patient survival and physicians’ ability to predict survival in NSCLC with brain metastases has improved significantly. The updated Lung-molGPA incorporating gene alteration data into the DS-GPA is a user-friendly tool that may facilitate clinical decision making and appropriate stratification of future clinical trials.

Treatment options and outcomes for glioblastoma in the elderly patient

Age remains the most powerful prognostic factor among glioblastoma (GBM) patients. Half of all patients with GBM are aged 65 years or older at the time of diagnosis, and the incidence rate of GBM in patients aged over 65 years is increasing rapidly. Median survival for elderly GBM patients is less than 6 months and reflects less favorable tumor biologic factors, receipt of less aggressive care, and comorbid disease. The standard of care for elderly GBM patients remains controversial. Based on limited data, extensive resection appears to be more beneficial than biopsy. For patients with favorable Karnofsky performance status (KPS), adjuvant radiotherapy (RT) has a demonstrated survival benefit with no observed decrement in quality of life. Concurrent and adjuvant temozolomide (TMZ) along with RT to 60 Gy have not been prospectively studied among patients aged over 70 years but should be considered for patients aged 65–70 years with excellent KPS. Based on the recent NOA-08 and Nordic randomized trials, testing for O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation should be performed routinely immediately after surgery to aid in adjuvant treatment decisions. Patients aged over 70 years with favorable KPS, or patients aged 60–70 years with borderline KPS, should be considered for monotherapy utilizing standard TMZ dosing for patients with MGMT-methylated tumors, and hypofractionated RT (34 Gy in ten fractions or 40 Gy in 15 fractions) for patients with MGMT-unmethylated tumors. The ongoing European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial will help clarify the role for concurrent TMZ with hypofractionated RT. For elderly patients with poor KPS, reasonable options include best supportive care, TMZ alone, hypofractionated RT alone, or whole brain RT for symptomatic patients needing to start treatment urgently. Given the balance between short survival and quality of life in this patient population, optimal management of elderly GBM patients must be made individually according to patient age, MGMT methylation status, performance score, and patient preferences.

Long‐term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer

Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow‐up.

Visual Outcome and Tumor Control After Conformal Radiotherapy for Patients With Optic Nerve Sheath Meningioma

PURPOSE Optic nerve sheath meningioma (ONSM) is a rare tumor that almost uniformly leads to visual dysfunction and even blindness without intervention. Because surgical extirpation carries a high risk of postoperative blindness, vision-sparing treatment strategies are desirable. METHODS AND MATERIALS We retrospectively reviewed the outcomes of 25 patients (25 optic nerves) with ONSM, treated at a single institution with conformal fractionated radiotherapy by either stereotactic photon or proton radiation. Primary endpoints were local control and visual acuity. RESULTS The patients presented with symptoms of visual loss (21) or orbital pain (3) or were incidentally diagnosed by imaging (3). The mean age was 44 years, and 64% were female patients. The indication for treatment was the development or progression of symptoms. Of the patients, 13 were treated with photons, 9 were treated with protons, and 3 received a combination of photons and protons. The median dose delivered was 50.4 gray equivalents (range, 45-59.4 gray equivalents). Median follow-up after radiotherapy was 30 months (range, 3-168 months), with 3 patients lost to follow-up. At most recent follow-up, 21 of 22 patients (95%) had improved (14) or stable (7) visual acuity. One patient had worsened visual acuity after initial postirradiation improvement. Of the 22 patients, 20 (95%) had no radiographic progression. Three patients had evidence of asymptomatic, limited retinopathy on ophthalmologic examination, and one had recurrent ONSM 11 years after treatment. CONCLUSIONS Highly conformal, fractionated radiation therapy for symptomatic primary ONSM provides tumor control and improvement in visual function in most cases, with minimal treatment-induced morbidity. Longer follow-up is needed to assess the durability of tumor control and treatment-related late effects.

Outcomes in stage I testicular seminoma: A population-based study of 9193 patients

Few studies have quantified temporal patterns of cause‐specific mortality in contemporary cohorts of men with early‐stage seminoma. Given that several management strategies can be applied in these patients, each resulting in excellent long‐term survival, it is important to evaluate associated long‐term sequelae. In particular, data describing long‐term risks of cardiovascular disease (CVD) are conflicting.

Outcomes in stage i testicular seminoma

Few studies have quantified temporal patterns of cause‐specific mortality in contemporary cohorts of men with early‐stage seminoma. Given that several management strategies can be applied in these patients, each resulting in excellent long‐term survival, it is important to evaluate associated long‐term sequelae. In particular, data describing long‐term risks of cardiovascular disease (CVD) are conflicting.

Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells

Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.