Pamela J. DiPiro

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Hodi and colleagues report the safety and efficacy of targeting angiogenesis and CTLA-4 in a phase I trial of 46 patients with metastatic melanoma, which revealed the influence of VEGF-A blockade on inflammation, lymphocyte trafficking, and immune regulation, and their synergistic therapeutic effects. Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8+ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7+/−/CD45RO+ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Cancer Immunol Res; 2(7); 632–42. ©2014 AACR.

CT tumor volume measurement in advanced non-small-cell lung cancer. Performance characteristics of an emerging clinical tool

RATIONALE AND OBJECTIVES Determine inter- and intraobserver variability of computed tomography (CT) tumor volume measurements in advanced non-small-cell lung cancer (NSCLC) patients treated in a Phase II clinical trial using chest CT. MATERIALS AND METHODS Twenty-three advanced NSCLC patients with a total of 53 measurable lung lesions enrolled in a Phase II, multicenter, open-label clinical trial of erlotinib were retrospectively studied with institutional review board approval. Two radiologists independently measured the tumor size, volume, and CT attenuation coefficient using commercially available volume analysis software. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess inter- and intraobserver agreement. RESULTS High CCCs (0.949-0.990) were observed in all types of measurements for interobserver agreement. The 95% limits of agreements for volume, unidimensional, and bidimensional measurements were (-26.0%, 18.6%), (-23.1%, 24.4%), and (-34.0%, 48.6%), respectively. Volume measurement had slightly higher CCC and narrower 95% limits of agreement compared to uni- and bidimensional measurements. CCCs for intraobserver agreement were high (range, 0.946-0.996) with CCC for volume being slightly higher than CCCs of uni- and bidimensional measurements. The smaller the tumor volume was, the larger the interobserver difference of CT attenuation. Location, morphology, or adjacent atelectasis had no significant impact on inter- or intraobserver variability. CONCLUSION CT tumor volume measurement in advanced NSCLC patients using clinical chest CT and commercially available software demonstrated high inter- and intraobserver agreement, indicating that the method may be used routinely in clinical practice.

Incidence of pulmonary embolism in oncologic outpatients at a tertiary cancer center

Incidence of pulmonary embolism (PE) for different cancer types in oncology outpatients is unknown. The purposes of the current study is to determine the incidence of PE in oncology outpatients and to investigate whether the incidence for PE is higher in certain cancers.

Volume and impact of second-opinion consultations by radiologists at a tertiary care cancer center: Data

RATIONALE AND OBJECTIVES Patients with cancer who are referred to a dedicated oncology center usually have undergone previous imaging studies that the oncologists typically desire to have reviewed by radiologists. Such reinterpretations can be complex and time-consuming, yet many institutions do not systematically account for them as part of the total workload. The purpose of this study was to ascertain the numbers and types of second-opinion consultations performed by radiologists at a tertiary care cancer center, and to assess their effect on work volume. MATERIALS AND METHODS A survey of referring clinicians was undertaken to evaluate the numbers and types of second-opinion consultations requested of radiologists at the Dana Farber Cancer Institute during a 12-month period. Consultations included review of studies from outside institutions, and cases from Dana Farber in which further comparison was needed. The number of consultations requiring additional tumor size measurements was tallied. The mean daily number of new studies interpreted by radiologists was used as a benchmark of work volume. RESULTS Radiologists performed 4,664 consultations during 254 workdays, interpreting a mean of 18 additional studies (range, 4-42) per day as a result of referrals for second opinion. These included 3,638 (78%) cross-sectional studies (ie, computed tomographic [CT], magnetic resonance [MR], and ultrasound [US] studies), 674 (14%) mammograms, 220 (5%) plain radiographs, 132 (3%) nuclear medicine scans, and one galactogram. Of the 4,664 consultations, 1,306 (28%) were performed to obtain tumor measurements, many of these involving five to 10 bidimensional calculations per study. A mean of 101 new examinations per day was performed by radiologists during the same 12-month period, including cross-sectional studies (CT and US scans) (56%), plain radiographs (34%), and mammograms (11%). MR imaging was not performed. CONCLUSION Second-opinion consultations increased the average daily work volume by 18%. This has implications for workforce, as well as for compensation in terms of relative value units and finances for this previously unquantified service.

Unsuspected pulmonary embolism in lung cancer patients: Comparison of clinical characteristics and outcome with suspected pulmonary embolism

PURPOSE Compare the clinical characteristics, rate of recurrent venous thromboembolism (VTE) and outcome of suspected and unsuspected pulmonary embolism (PE) detected on computed tomography in patients with lung cancer. METHODS In this IRB-approved retrospective study, 77 patients [38 men, 39 women; mean age 64 (range, 35-90)] with lung cancer who developed PE between January 2004 and December 2009 were identified using research patient data registry and medical records. Patients with suspected (45/77, 58%) and unsuspected (32/77, 42%) PE were compared for the characteristics, treatment of PE, and rate of recurrent VTE using Fishers exact test. The survival was compared using log-rank test, and Cox proportional hazards regression models were applied for univariate and multivariable analyses. RESULTS Most cases of PE were found in patients undergoing chemotherapy (79%) and with metastatic disease (70%). Suspected PE more commonly involved main/lobar pulmonary arteries (33/45, 73% vs. 9/32, 28%), while unsuspected PE more frequently involved of segmental/subsegmental arteries (p=0.0001). All 11 cases of squamous cell carcinoma had suspected PE. Suspected and unsuspected PE did not differ in terms of age, gender, presence of metastatic disease at the time of PE or treatment for PE. 44/45 (98%) patients with suspected PE and 30/32 (94%) patients with unsuspected PE were treated for PE, mostly with anticoagulation (68/74, 92%). Recurrent VTE was seen in 20% (9/45) of suspected PE and 19% (6/32) of unsuspected PE (p=1.00). Median survival after PE was 5.6 months in suspected group and 6.2 month in unsuspected group, without significant difference by univariate or multivariate analyses. CONCLUSION Although unsuspected PE more frequently involved peripheral pulmonary arteries, the treatments of PE, bleeding complications, rates of recurrent VTE, and survival after PE were similar for clinically suspected and unsuspected PE.

Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer

BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

Metastatic patterns of breast cancer subtypes: What radiologists should know in the era of personalized cancer medicine

There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2-expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance.

CT and PET/CT findings of T-cell lymphoma.

OBJECTIVE The purpose of this study was to describe the extranodal features of T-cell lymphoma at CT and PET/CT. CONCLUSION The extranodal features of T-cell lymphoma are not specific and usually cannot be used to differentiate T-cell lymphoma from other aggressive types of lymphoma. Noncutaneous subtypes frequently manifest with visceral involvement. The goal of CT in initial staging is to exclude visceral involvement. Evidence on the utility of PET/CT is promising, showing high diagnostic value in evaluation of occult disease and treatment response, but the role of PET/CT is evolving.

Revisiting the relationship between tumour volume and diameter in advanced NSCLC patients: An exercise to maximize the utility of each measure to assess response to therapy

AIM To revisit the presumed relationship between tumour diameter and volume in advanced non-small-cell lung cancer (NSCLC) patients, and determine whether the measured volume using volume-analysis software and its proportional changes during therapy matches with the calculated volume obtained from the presumed relationship and results in concordant response assessment. MATERIALS AND METHODS Twenty-three patients with stage IIIB/IV NSCLC with a total of 53 measurable lung lesions, treated in a phase II trial of erlotinib, were studied with institutional review board approval. Tumour volume and diameter were measured at baseline and at the first follow-up computed tomography (CT) examination using volume-analysis software. Using the measured diameter (2r) and the equation, calculated volume was obtained as (4/3)πr(3) at baseline and at the follow-up. Percent volume change was obtained by comparing to baseline for measured and calculated volumes, and response assessment was assigned. RESULTS The measured volume was significantly smaller than the calculated volume at baseline (median 11,488.9 mm(3) versus 17,148.6 mm(3); p < 0.0001), with a concordance correlation coefficient (CCC) of 0.7022. At follow-up, the measured volume was once again significantly smaller than the calculated volume (median 6573.5 mm(3) versus 9198.1 mm(3); p = 0.0022), with a CCC of 0.7408. Response assessment by calculated versus measured volume changes had only moderate agreement (weighted κ = 0.545), with discordant assessment results in 20% (8/40) of lesions. CONCLUSION Calculated volume based on the presumed relationship significantly differed from the measured volume in advanced NSCLC patients, with only moderate concordance in response assessment, indicating the limitations of presumed relationship.

Image-guided core breast biopsy of ductal carcinoma in situ presenting as a non-calcified abnormality

OBJECTIVE Ductal carcinoma in situ (DCIS) typically presents as calcifications which are detected mammographically. Our aim was to evaluate the less common presentations of ductal carcinoma in situ diagnosed by image-guided core biopsy and correlate with histopathologic diagnoses. METHODS AND MATERIAL Imaging and histopathologic findings were retrospectively reviewed in 11 patients with ductal carcinoma in situ diagnosed at core biopsy that presented as noncalcified radiographic abnormalities. RESULTS Mammography showed non-calcified, circumscribed nodules, ill-defined nodules and architectural distortion. In two patients, no mammographic abnormality was detected. Sonography showed circumscribed, round or oval, solid masses; irregular, heterogeneous masses; and a tubular structure. Histopathologic diagnoses included multiple architectural subtypes and ranged from low to high nuclear grade. CONCLUSION Although image-guided core biopsy diagnosis of ductal carcinoma is typically made when sampling calcifications, DCIS can be diagnosed following biopsy of non-calcified masses or distortion. There is no correlation between histopathologic subtype and radiologic appearance.