IU Indianapolis ScholarWorks :: Browsing by Author "Einhorn, Lawrence"

Browsing by Author "Einhorn, Lawrence"

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Adverse Health Outcomes among U.S. Testicular Cancer Survivors after Cisplatin-Based Chemotherapy vs. Surgical Management
(Oxford, 2019-10) Agrawal, Vaibhav; Dinh, Paul C., Jr.; Fung, Chunkit; Monahan, Patrick O.; Althouse, Sandra K.; Norton, Kelli; Cary, Clint; Einhorn, Lawrence; Fossa, Sophie D.; Adra, Nabil; Travis, Lois B.; Medicine, School of Medicine
We evaluated for the first time adverse health outcomes (AHOs) among U.S. testicular cancer survivors (TCS) given chemotherapy (n = 381) vs. surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy’s impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in 3 or 4 cycles (BEPX3, n = 235; BEPX4, n = 82). Incidence of ≥ 3 AHOs was lowest in surgery-only TCS and increased with BEPX3, BEPX4 and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P<0.0001). Multivariate modeling assessed associations of risk factors and treatment with hearing impairment, tinnitus, peripheral neuropathy, and Raynaud phenomenon. Risk for each AHO significantly increased with both increasing chemotherapy burden (P < 0.0001) and selected modifiable risk factors (P < 0.05): hypertension (OR = 2.40) and noise exposure (OR ≥ 2.3) for hearing impairment; noise exposure for tinnitus (OR ≥ 1.69); peripheral vascular disease for neuropathy (OR = 8.72), and current smoking for Raynaud phenomenon (OR = 2.41). Clinicians should manage modifiable risk factors for AHOs among TCS.
Carboplatin and Etoposide With or Without Palifosfamide in Untreated Extensive-Stage Small-Cell Lung Cancer: A Multicenter, Adaptive, Randomized Phase III Study (MATISSE)
(ASCO, 2017-08) Jalal, Shadia I.; Lavin, Philip; Lo, Gregory; Lebel, Francois; Einhorn, Lawrence; Medicine, School of Medicine
Purpose To evaluate the efficacy of the addition of palifosfamide to carboplatin and etoposide in extensive stage (ES) small-cell lung cancer (SCLC). Patients and Methods MATISSE was a randomized, open-label, adaptive phase III study. Previously untreated patients with ES SCLC were randomly assigned in a 1:1 fashion to receive carboplatin at area under the serum concentration-time curve 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days (CE) or carboplatin at area under the serum concentration-time curve 4 on day 1 plus etoposide 100 mg/m2 per day plus palifosfamide 130 mg/m2 per day on days 1 to 3 every 21 days (PaCE). The primary end point was overall survival. Results In all, 188 patients were enrolled; 94 patients received CE and 94 patients received PaCE. The median age on both arms was 61 years. Six cycles of chemotherapy were completed on both arms of the study by approximately 50% of the patients. Serious adverse events were documented and did not differ significantly between patients receiving PaCE and those receiving CE. Median overall survival was similar between both arms with 10.03 months on PaCE and 10.37 months on CE (P = .096). Conclusion The addition of palifosfamide to CE failed to improve survival in ES SCLC.
Controversies in the management of clinical stage 1 testis cancer
(Canadian Urological Association, 2020-11) Nason, Gregory J.; Chung, Peter; Warde, Padraig; Huddart, Robert; Albers, Peter; Kollmannsberger, Christian; Booth, Christopher M.; Hansen, Aaron R.; Bedard, Philippe L.; Einhorn, Lawrence; Nichols, Craig; Rendon, Ricardo A.; Wood, Lori; Jewett, Michael A.S.; Hamilton, Robert J.; Medicine, School of Medicine
In November 2018, The Canadian Testis Cancer Workshop was convened. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician’s assistants, residents and fellows, nurses, patients and patient advocacy groups. One of the goals of the workshop was to discuss the challenging areas of testis cancer care where guidelines may not be specific. The objective was to distill through discussion around cases, expert approach to working through these challenges. Herein we present a summary of discussion from the workshop around controversies in the management of clinical stage 1 (CS1) disease. CS1 represents organ confined non-metastatic testis cancer that represents approximately 70-80% of men at presentation. Regardless of management, CS1 has an excellent prognosis. However, without adjuvant treatment, approximately 30% of CS1 nonseminomatous germ cell tumors (NSGCT) and 15% of CS1 seminoma relapse. The workshop reviewed that while surveillance has become the standard for the majority of patients with CS1 disease there remains debate in the management of patients at high-risk of relapse. The controversy in the management of CS1 testis cancer surrounds the optimal balance between the morbidity of overtreatment and the identification of patients who may derive most benefit from adjuvant treatment. The challenge lies in a shared decision process where discussion of options extends beyond the simple risk of relapse but to include the long-term toxicities of adjuvant treatments and the favorable cancer-specific survival.
Long-Term Oncologic Outcomes after Primary Retroperitoneal Lymph Node Dissection: Minimizing the Need for Adjuvant Chemotherapy
(AUA, 2020) Douglawi, Antoin; Calaway, Adam; Tachibana, Isamu; Barboza, Marcelo Panizzutti; Speir, Ryan; Masterson, Timothy; Adra, Nabil; Foster, Richard; Einhorn, Lawrence; Cary, Clint; Urology, School of Medicine
Objective: To analyze the oncological outcomes of men undergoing primary RPLND and characterize the use of adjuvant chemotherapy and template dissections. Methods: Retrospective review of Indiana University testis cancer database identified patients who underwent a primary RPLND between 01/2007 and 12/2017. Patients and providers were contacted to obtain information regarding adjuvant therapy, recurrence, and survival. Primary outcome was recurrence-free survival (RFS). Kaplan-Meier curves assessed survival differences stratified by pathologic stage, template of dissection, and use of adjuvant chemotherapy. Results: Overall, 274 patients were included. Most men presented with CS-I disease (214, 78%). A modified unilateral template was performed in 257 (94%) and bilateral template in 17 (6%). Overall, 148 (54%) and 126 (46%) of men had Pathologic Stage I (PS-I) and PS-II disease, respectively. Thirteen patients (10%) with PS-II disease were treated with adjuvant chemotherapy. With a median follow-up was 55 months, only 33 (12%) patients recurred. Of the 113 patients with PS-II disease who did not receive chemotherapy, 21 (19%) relapsed and 81% were cured were surgery alone and never recurred. No difference in RFS was noted between modified and bilateral template dissections. Conclusions: The use of adjuvant chemotherapy has been minimal over the past decade. The majority (81%) of men with PS-II disease were cured with RPLND alone and were able to avoid chemotherapy. Modified unilateral template dissection provided excellent oncologic control while minimizing morbidity.
Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin Based Combination Chemotherapy
(Hindawi, 2015-09) Ranganath, Praveen; Einhorn, Lawrence; Albany, Costantine; Medicine, School of Medicine
Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect of multiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of these side effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curable neoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nausea and vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)3 receptor antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and delayed CINV. Mechanism and pattern of CINV with multiday chemotherapy may differ from those in single day chemotherapy and therefore efficacy of antiemetic drugs as observed in single day chemotherapy may not be applicable. There are only few randomized clinical trials with special emphasis on multiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose, and duration of the newer agents and combinations in multiday cisplatin based chemotherapy.
A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors
(Springer Nature, 2019-08) Sharman, Jeffrey P.; Wheler, Jennifer J.; Einhorn, Lawrence; Dowlati, Afshin; Shapiro, Geoffrey I.; Hilton, John; Burke, John M.; Siddiqi, Tanya; Whiting, Nancy; Jalal, Shadia I.; Medicine, School of Medicine
Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.
“Testicular Cancer: A Model for a Curable Cancer”
(2014-02-27) Einhorn, Lawrence
Lawrence H. Einhorn, M.D., IUPUI Distinguished Professor and Lance Armstrong Foundation Professor of Oncology at the IU School of Medicine, is widely regarded as the physician who cured testicular cancer in 95 percent of cases through a revolutionary chemotherapy regimen seen as responsible for a dramatic improvement in what previously had been a devastating and rapidly fatal disease. Dr. Einhorn is also a researcher with the IU Melvin and Bren Simon Cancer Center.
Treatment of CD30-Expressing Germ Cell Tumors and Sex Cord Stromal Tumors with Brentuximab Vedotin: Identification and Report of Seven Cases
(AlphaMed Press, 2018-03) Albany, Costantine; Einhorn, Lawrence; Garbo, Lawrence; Boyd, Thomas; Josephson, Neil; Feldman, Darren R.; Department of Medicine, IU School of Medicine
BACKGROUND: Cytotoxic therapy for relapsed and refractory germ cell tumors or metastatic sex cord stromal tumors is rarely effective and is often accompanied by high adverse event rates. Expression of CD30 has been observed in testicular cancers, and patients with CD30-expressing embryonal carcinomas have worse progression-free survival and overall survival than those with CD30-negative tumors. The objective of this study (NCT01461538) was to characterize the antitumor activity of brentuximab vedotin in patients with CD30-expressing nonlymphomatous malignancies. Enrolled patients included seven patients with relapsed or refractory germ cell tumors or metastatic sex cord stromal tumors described in this case series. MATERIALS AND METHODS: Forty patients with relapsed or refractory germ cell tumors, metastatic sex cord stromal tumors, or testicular tumors were screened for CD30 expression; 14 patients had tumors that expressed CD30. Seven patients with CD30-expressing testicular cancer were enrolled in the treatment study: five patients with germ cell tumors, one patient with a Leydig cell tumor, and one patient with a Sertoli cell tumor. Patients were treated with brentuximab vedotin at initial doses of 1.8 or 2.4 mg/kg every 3 weeks. Response assessments were performed at cycles 2 and 4 and every 4 cycles thereafter while the patient was receiving treatment. RESULTS: Two of seven patients achieved an objective response, including one durable complete response and one partial response at a single time point. Both responding patients had germ cell tumors. Treatment with brentuximab vedotin was generally well tolerated. CONCLUSION: Treatment of relapsed or refractory germ cell tumors with brentuximab vedotin can induce durable responses with a manageable toxicity profile. IMPLICATIONS FOR PRACTICE: This case series of seven patients with relapsed or refractory CD30-expressing germ cell tumors (GCTs) or sex cord stromal tumors demonstrates that brentuximab vedotin has activity against GCTs and is well tolerated in heavily pretreated patients with these aggressive tumor types. One patient achieved a complete response that has been durable for almost 4 years since the discontinuation of treatment with brentuximab vedotin. Therefore, brentuximab vedotin may be a valuable option for physicians who care for this difficult-to-treat patient population.
Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
(American Association for Cancer Research, 2017-07-01) Wheeler, Heather E.; Gamazon, Eric R.; Frisina, Robert D.; Perez-Cervantes, Carlos; El Charif, Omar; Mapes, Brandon; Fossa, Sophie D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Fung, Chunkit; Kollmannsberger, Christian; Kim, Jeri; Mushiroda, Taisei; Kubo, Michiaki; Ardeshir-Rouhani-Fard, Shirin; Einhorn, Lawrence; Cox, Nancy J.; Dolan, M. Eileen; Travis, Lois B.; Medicine, School of Medicine
Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.

Browsing by Author "Einhorn, Lawrence"

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