Ronald J. Scheff

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

OBJECT The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. METHODS A total of 30 patients with recurrent malignant glioma were included in the current study. RESULTS The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. CONCLUSIONS The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

Adoptive cellular immunotherapy for the treatment of malignant gliomas.

UNLABELLED The median survival for adults with recurrent primary malignant gliomas is 56 weeks following surgery, radiation, and chemotherapy. Generally, reoperation can extend the median survival an additional 26-32 weeks. We have developed an aggressive treatment program that utilizes low doses of interleukin-2 (IL-2) combined with ex vivo activated killer cells (LAK) infused via an indwelling catheter placed into the surgical resection cavity. Autologous leukocytes were collected during a standard 3-4 h, outpatient leukapheresis procedure, then activated ex vivo for 4-5 days with high doses of IL-2. The treatment protocol consisted of two 2-week cycles of therapy over a 6-week period. Patients with stable disease or objective response on follow-up MRI scans were retreated at 3-month intervals. Acute and cumulative IL-2-related toxicities were observed, but limited, and included fever, headache and transient neurologic irritation. Corticosteroid levels and usage were strictly controlled during immunotherapy, although higher doses were used intermittently to mitigate toxicity. Biologic changes included lymphocytic infiltration, regional eosinophilia, tumor necrosis, and the localized production of IL-2, IFN-gamma and IL-12, demonstrated by in situ hybridization and immunohistochemistry. SUMMARY IL-2 plus autogeneic LAK cells can be safely administered intracavitary to treat high grade primary brain tumors with limited toxicity within the central nervous system. Six out of 28 patients had long-term survival of greater than 2 years post-reoperation plus immunotherapy with 2 patients alive over 8 years. The presence of a marked regional eosinophilia appeared to correlate with increased survival and may be predictive of a biologic and therapeutic response. Regional adoptive immune therapy was well tolerated and should be considered an option for patients with high-grade tumors refractive to standard therapeutic approaches.

Employment after a breast cancer diagnosis: a qualitative study of ethnically diverse urban women.

Employment status is related to treatment recovery and quality of life in breast cancer survivors, yet little is known about return to work in immigrant and minority survivors. We conducted an exploratory qualitative study using ethnically cohesive focus groups of urban breast cancer survivors who were African-American, African-Caribbean, Chinese, Filipina, Latina, or non-Latina white. We audio- and video-recorded, transcribed, and thematically coded the focus group discussions and we analyzed the coded transcripts within and across ethnic groups. Seven major themes emerged related to the participants’ work experiences after diagnosis: normalcy, acceptance, identity, appearance, privacy, lack of flexibility at work, and employer support. Maintaining a sense of normalcy was cited as a benefit of working by survivors in each group. Acceptance of the cancer diagnosis was most common in the Chinese group and in participants who had a family history of breast cancer; those who described this attitude were likely to continue working throughout the treatment period. Appearance was important among all but the Chinese group and was related to privacy, which many thought was necessary to derive the benefit of normalcy at work. Employer support included schedule flexibility, medical confidentiality, and help maintaining a normal work environment, which was particularly important to our study sample. Overall, we found few differences between the different ethnic groups in our study. These results have important implications for the provision of support services to and clinical management of employed women with breast cancer, as well as for further large-scale research in disparities and employment outcomes.

Non–Small-Cell Lung Cancer: Treatment of Late Stage Disease: Chemotherapeutics and New Frontiers

Systemic therapy should be considered in patients with advanced non-small cell lung cancer (NSCLC) who are no longer amenable to local therapies. Systemic therapy has been shown to improve survival and preserve quality of life in patients with a reasonable performance status. In unselected patients, the standard of care for initial therapy remains platinum-based chemotherapy. At progression, further treatment typically consists of the sequential administration of single-agent therapy, which has also been shown to improve survival and reduce cancer-related symptoms. Molecular biomarkers are essential to guide targeted agents. This analysis requires ample tumor DNA; thus adequate biopsy samples are critical to guide therapeutic options. More biomarkers are currently being validated and may potentially have specific targeted therapy. In the near future, it is likely that rapid multiplexed genotype testing will help reduce the need for large amounts of tumor for analysis and will promote personalized cancer therapy. We review recent changes in the definition of stage IV NSCLC and review current and future systemic therapeutic approaches for patients with advanced disease.

Treatment of refractory recurrent malignant glioma with adoptive cellular immunotherapy: a case report

We report the successful treatment of a patient with recurrent malignant glioma with adoptive cellular immunotherapy. The patient is a young adult with recurrent progressive disease refractory to aggressive multi-modality therapy including repetitive surgical resection, radiation, radiosurgery and chemotherapy. He received multiple courses of local administration of autologous lymphokine-activated killer (LAK) cells in combination with a low dose of interleukin-2 (IL-2) through an Ommaya reservoir-catheter system. The side-effects of this treatment were limited and manageable. The patient achieved a complete remission, as demonstrated by MRI and confirmed by glucose-positron emission tomography (PET) imaging 11 months after initiation of immune therapy. Twenty-six months later, the patient is still in remission with improving performance status. Adoptive cellular immunotherapy utilizing autologous LAK cells with low dose IL-2 appears to be a safe and effective therapy for a subset of patients with primary, recurrent or progressive malignant glioma following conventional therapy.

Therapy of Advanced Non–Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan

Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non-small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2-expressing tumors.

Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I–inhibiting Antibody–Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan

Purpose: We evaluated a Trop-2–targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients. Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1–7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections. Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711–9. ©2017 AACR.

The effect of tetrathiomolybdate on circulating endothelial progenitor cells in patients with breast cancer at high risk of recurrence.

Abstract #1036 Background: Endothelial progenitor cells are critical to tumor angiogenesis and are increased in breast cancer patients. Copper is required for angiogenesis, and pre-clinical data suggest that tetrathiomolybdate (TM), a copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. We sought to measure circulating endothelial progenitor cells (CEPCs) in patients at high risk of breast cancer recurrence and to evaluate the effect of copper depletion on CEPCs.
 Methods: This analysis is part of an ongoing phase II study of TM in breast cancer patients at high risk of recurrence defined as Stage III or IV with no evidence of disease. All therapy other than hormonal was completed at least 6 weeks prior to study. Treatment: TM 180 mg daily to achieve a target ceruloplasmin (Cp) level of 5-15 mg/dL (copper depletion), and then 100 mg daily. We monitored levels of CEPCs (CD45dim, CD133+, VEGFR2+), CEA, CA15-3, and Cp at baseline and monthly. CEPCs were also measured in 6 healthy controls.
 Results: To date we have enrolled 16 patients with a median age of 51 years (range: 29-64). 14 had a history of Stage III disease, while 2 were considered to be Stage IV with no evidence of disease. The median number of positive lymph nodes among Stage III patients was 7 (1-42), with 2 patients having received neoadjuvant therapy. The median baseline Cp level was 28 mg/dL (21-41). Among 12 patients who have reached target Cp, the median time to target was 1 month (1-3 months). The median follow-up of the 4 patients who have not yet achieved target is 2.5 months. 1 of these discontinued treatment before reaching target. The median baseline CEPCs was lower in patients than healthy controls: 0.022 cells/μL (0.000-0.286) vs. 0.123 cells/μL (0.058-0.418); p=0.03. There was no statistically significant change in CEPCs from baseline over time.
 One patient was diagnosed with recurrent breast cancer at month 10. A rise in her CEPCs preceded a rise in a CEA and overt relapse by 1 and 5 months, respectively.
 Toxicity: Grade 3/4 neutropenia occurred in 3 patients. TM was held, and this resolved 5-13 days later, after which TM was resumed. No other grade 3/4 toxicity was observed. One patient discontinued TM due to diarrhea attributed to the lactose used in the compounding of TM.
 Conclusions: TM is well tolerated in breast cancer patients. We postulate that the increased CEPCs noted in one patient at month 4, 6 months prior to overt relapse, could represent the “turning on” of an angiogenic switch, resulting in an outpouring of CEPCs to the new site of metastasis. The trial is ongoing, and with additional follow-up other trends might emerge.
 Supported by Komen for the Cure Foundation, Anbinder Foundation, NY Community Trust and Breast Cancer Alliance of Greenwich. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1036.

Abstract CT413: Lutetium-177-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) for metastatic non-prostate solid tumors

Introduction: PSMA is a non-secreted cell-surface protein that is expressed by the neovascular endothelium of most solid tumors (but not by vascular endothelium of normal tissue), making it a candidate for vascular-targeted therapy. The purpose of this study was to define the change in tumor perfusion and cellularity after 177Lu-J591 therapy in patients (pts) with advanced non-prostate solid tumors and PSMA expression as determined by radionuclide imaging (with 111In-J591) and/or by immunohistochemistry (IHC). Of note, radiolabeled J591 is hepatically cleared (negating accurate assessment of liver metastases by J591 imaging). Methods: In this pilot study, following confirmation of PSMA expression by 111In-J591 imaging and/or IHC of tumor neovasculature), 14 pts in 2 cohorts received 177Lu-J591 therapy (7 received a single dose at 70 mCi/m2; 7 received 2 fractionated doses at 35 mCi/m2 each). Pts underwent dynamic contrast enhanced (DCE)-MRI and diffusion weighted imaging (DWI) at baseline, then repeated at 1, 4, 8, and 12 wks post treatment to evaluate tumor perfusion (DCE-MRI) and cellularity (Apparent Diffusion Coefficient (ADC) values from DWI). Values were compared with paired t-testing using Wilcoxon signed-rank test for significance. Results: Among the 14 treated pts, tumor types included: lung (5), bladder (2), pancreas (2), colon, GE junction, renal, ovarian carcinomas and melanoma (1 each). Median age was 61.5 with a median of 3 prior therapies including 5 with prior anti-angiogenic agents; 8 pts received prior radiation. Metastatic sites included: bone, lymph nodes, liver, lung, brain, other. 11 of 14 pts had PSMA expression confirmed by imaging, 3 additional by IHC of archival tumor tissue (with liver metastases). DCE-MRI demonstrated that treatment significantly affected tumor perfusion, with decreased perfusion at the 1-wk (n=11, p=0.03) and 4-wk (n=6, p=0.01) post 177Lu-J591 time points. Compared to baseline, DCE slope was lower than baseline at 1 wk (p=0.045) and 4-wk (p=0.02). Week 8 (n=4) was non-significant for both % change and DCE slope and only 2 pts completed the wk 12 time point. In evaluation of cellularity, 5 of 9 pts had an increase in ADC at either the 1- or 4-wk time point (1 stable, 3 decreased). However, paired comparisons at individual time points were non-significant. Conclusion: Anti-PSMA radioimmunotherapy targeting tumor neovasculature is feasible using 177Lu-J591 and can alter tumor perfusion and cellularity, including in those with prior exposure to anti-angiogenic therapy and/or radiation. Refinement in patient selection with improved imaging (anti-PSMA immuno-PET) is ongoing. Citation Format: Orrin Pail, Gurveen Kaur, Jonathan Dyke, Yuliya Jhanwar, Paul Christos, Allyson Ocean, Manish Shah, Tsiporah Shore, Bryan Schneider, Ronald Scheff, Himisha Beltran, Douglas Ballon, Brian Robinson, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Lutetium-177-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) for metastatic non-prostate solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT413. doi:10.1158/1538-7445.AM2014-CT413

Non-Small-Cell Lung Cancer: Treatment of Late Stage Disease: Chemotherapeutics and New Frontiers (Seminars in Interventional Radiology (2013) 30, 2 (191))

[This corrects the article DOI: 10.1055/s-0033-1342961.].