Standard Multiagent Chemotherapy Research Articles

Targeted therapy using larotrectinib and venetoclax for the relapsed/refractory T-cell acute lymphoblastic leukemia harboring a cryptic ETV6-NTRK3 fusion.

Outcomes for patients with relapsed and refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are dismal, with few available treatments. Recently, identification of cancer patients harboring neurotrophic tropomyosin receptor kinase (NTRK) gene fusions is constantly increasing, especially with the advent of NTRK inhibitors. However, the role of ETV6-NTRK3 in T-ALL has not been investigated. This case represented the first detailed report of T-ALL patient harboring a cryptic ETV6-NTRK3 fusion with an unfavorable prognosis, not only because of leukemia resistant to the standard multiagent chemotherapy but also early relapse after allo-HSCT. Acquired EP300 mutation was found at relapse, which could explain the cause of recurrence and affect the follow-up treatment. Combined targeted therapy like larotrectinib allied with pan-targeted BCL-2 inhibitor venetoclax, may be a potential maintenance treatment in R/R ETV6-NTRK3 positive leukemia after allo-HSCT. The leukemic clonal evolution might be revealed through transcriptome sequencing and overcome by drugs with universal targets. Our case demonstrated that both comprehensive profiling techniques (such as transcriptome sequencing, multiparameter flow cytometry, and digital droplet polymerase chain reaction) and a multimodality treatment strategy were critical for anticipating an early relapse and personalized therapy of R/R T-cell leukemia.

Peripheral Neuropathy in Children with High Risk Hodgkin Lymphoma (HL): The Role of Protocol-Stipulated Dose Modification in the Children's Oncology Group (COG) AHOD1331 Study

Background Peripheral neuropathy (PN) is commonly associated with several classes of chemotherapy, including vinca alkaloids and the novel anti-CD30-directed antibody-drug conjugate, Brentuximab vedotin (Bv). The drug moiety in Bv, monomethyl auristatin E, a potent microtubule tubulin inhibitor, is known to cause PN. In the 2018 Echelon-1 study, rates of PN among adults with advanced stage HL were 67% in the Bv arm as compared to 43% in the control arm (Connors, 2018) with dose modifications at the discretion of the treating physician of 66% for Bv and 57% for vinblastine (VBL). We examined rates of PN and use of protocol-stipulated dose modification in the COG AHOD1331, a Phase 3 randomized comparison of standard multi-agent chemotherapy (ABVE-PC) vs. Bv-AVE-PC among children and adolescents with high risk HL (Castellino, 2022). The combination of vincristine (VCR) with Bv warrants the formal study of PN in this trial. Methods Eligible patients (pts) ages 2-21 years with high risk HL were enrolled from 2015-2019 (NCT02166463). After randomization, pts received 5 cycles of chemotherapy. Pts in the standard (std) arm received VCR on Day 1 and 8 of each 21-day treatment cycle; pts in the experimental (exp) arm received Bv (1.8 mg/kg) on Day 1 and VCR on Day 8. Clinician grading of PN was required at each cycle, using the Balis PN Scale, with protocol-stipulated dose modifications of VCR preceding modification of Bv in cases of PN > grade 2. Rates of PN were calculated by treatment cycle by study arm. Dose modifications were summarized for each drug by treatment cycle. Median time to first dose modification was estimated by treatment arm. A Cox model estimated hazard ratios (HR) and 95% confidence intervals (CI) for dose modifications by treatment arm and pt and clinical characteristics. Progression-free survival (PFS) was compared with Log-rank test by study arms and within arm by presence or absence of PN. Results 587 pts were enrolled on the study. While the proportion of pts overall developing PN did not differ by study arm (19%, p=0.86), dose modification of Bv, VCR, or both occurred more frequently on the exp arm (50/298, 16.8%) than on the std arm (12/289, 4.2%). Among pts on the exp arm, Bv was dose modified in 8% of pts; VCR was dose modified in 13.4% of pts. The median time to first dose modification was 40.8 days (31.5-73.5) for the exp arm vs. 75.5 days (59.0-94.8) for the std arm (p=.0043). During cycle 5, the rate of any PN was 3.1% in the exp arm vs. 7.8% in the std arm. Compared to the std arm, the HR for dose modification was 5.4 in the exp arm (95% CI, 2.3-12.6, p<0.0001); none of the other pt or disease characteristics were significantly associated with dose modification of the tubulin inhibitors. PFS was significantly better in the exp arm and did not differ by PN status (Figure). Conclusions The rate of dose modifications for PN was consistent with protocol-specified dose modification among children and adolescents treated with known tubulin inhibitors as part of a multi-drug regimen for high risk HL. The strategy to preserve Bv dose in the experimental arm was successful. Overall rates of PN were substantially lower than previously reported in adults treated with Bv. While there were no significant differences in the rate of PN between study arms, we found shorter median time to dose modification in the exp arm, corresponding to the second treatment cycle, as compared to the 3rd cycle for the std arm. Despite dose modifications of vincristine and Bv as management strategies for PN in the experimental arm, patients treated with Bv-AVEPC had superior disease control in children with high-risk HL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 3003: The effects of autophagy inhibition on HNSCC sensitivity to CTX

Abstract Background: Cetuximab (CTX) is a monoclonal antibody commonly used in the treatment of head and neck squamous cell carcinomas (HNSCCs) that acts by targeting the epidermal growth factor receptor (EGFR). Addition of CTX to standard multi-agent chemotherapy only slightly improves the response rate from 20% to 36%, highlighting the urgent need for improved treatment. Autophagy is a naturally occurring mechanism activated within cells to protect them from harsh conditions or stress but can also provide cancerous cells with protection against further treatment attempts. Here, we examine the efficacy of combining CTX with the autophagy inhibitor, SAR405, as well as investigating the specific mechanism of CTX-induced autophagy. Methods: To measure autophagy, we utilized the Promega LC3 reporter assay, Western blotting for LC3, immunofluorescence for LC3, and an acridine orange assay. We ran our assays using the HNSCC cell lines A253 (HPV-), UM-SCC1 (HPV+), and its CTX-resistant derivative, UM-SCC1-C5 (HPV+). Clonogenic assays were run to measure colony formation, cell counting kit 8 (CCK8) assays to determine cell survival, and flow cytometry to investigate cell cycle status. Results: In this study, we first were able to demonstrate that CTX can activate pro-survival autophagy. CTX-treated cells had higher LC3 flux and more LC3 puncta than control cells as assessed by western blot and immunofluorescence staining, respectively. CTX-resistant cells demonstrated higher basal LC3 flux compared to the CTX-sensitive parental cells. We also discovered that the use of the autophagy inhibitor, SAR405, could help improve tumor response when combined with CTX. The addition of SAR405 to CTX treatment led to a decrease in colony formation and a decrease in cell survival, overcoming resistance to CTX. Interestingly, we discovered that SAR405 alone led to cell cycle arrest in the G1 phase but did not lead to a statistically significant decrease in cell survival compared to the control, showing that SAR405 is able to arrest cell growth but is not cytotoxic. Finally, knockdown of EGFR or LAPTM4B prevented CTX-induced activation of autophagy. Conclusion: Through our work, we have been able to demonstrate that CTX is able to activate autophagy, and that this initiation of autophagy plays a cytoprotective role in HNSCC cells. The addition of the autophagy inhibitor SAR405 improved response to CTX treatment. The promising results obtained thus far open the door to future studies investigating the efficacy of combining CTX with more specific autophagy inhibitors. Citation Format: Samantha T. Bradley, Yong-Syu Lee, Justin H. Skiba, Jaimee Eckers, Adam D. Swick, Rong Hu, Kwang P. Nickel, Zafer Gurel, Pippa F. Cosper, Randall J. Kimple. The effects of autophagy inhibition on HNSCC sensitivity to CTX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3003.

SAT-LB91 Asparaginase Induced Severe Hypertriglyceridemia Requiring Multiple Plasmapheresis Sessions

Background: Asparaginase (ASP) is an essential component of chemotherapy for acute T-cell lymphoblastic lymphoma (T-ALL). Hypertriglyceridemia (HTG) is a known side effect of ASP therapy in children and adults (incidence up to 67 and 12.5%, respectively). The mechanism of HTG is multifactorial and involves lipoprotein lipase (LPL) suppression. Acute pancreatitis can occur in 13% of patients. There are no treatment guidelines currently available for ASP-induced HTG. Clinical Case: A 33 year old male with history of prediabetes, HTG and T-ALL being treated with CALGB 10403 chemotherapy protocol (vincristine, methotrexate, cytarabine and pegylated-ASP) presented to the ED with acute onset abdominal pain radiating to the back with associated nausea. He denied alcohol use. Home medications included fenofibrate, metformin and atorvastatin. His TG level prior to initiating chemotherapy was 454 mg/dL (ref range < 150) with an HbA1C of 6.5%. Upon presentation; TG level was 11,650 mg/dL, lipase was 563 U/L (13-60) with CT abdomen findings suggestive of mild pancreatitis. He was treated in the ICU with insulin drip at 0.05 - 0.1 unit/kg/hr with repeat TG level 6,490 mg/dL after 48 hours. He eventually required 5 serial plasmapheresis sessions over a 10 day hospital course in order to achieve a goal TG level under 500 mg/dL. Conclusion: ASP is part of standard multiagent chemotherapy for patients with ALL however poses the risk of developing severe HTG. This side effect may be explained by multiple mechanisms including increased synthesis of very low-density lipoprotein (VLDL), decreased LPL activity as a result of an increase in the apoCIII/apoCII ratio, and increase in serum chylomicrons. Studies have shown patients who had extreme HTG had a higher frequency of ApoE3/4 phenotype, suggesting that screening for ApoE polymorphism may identify patients at high risk for developing this. HTG secondary to ASP is often asymptomatic, with severe elevations in TG levels observed around 10 days after the 3rd administration of ASP and resolving 2-3 weeks after drug discontinuation. There are no treatment guidelines for ASP-associated HTG as there is no single typical clinical course. Management for severe HTG includes insulin infusion and plasmapheresis. Insulin rapidly activates LPL leading to mean TG reduction of 50% within the first 24 hours as compared to 66% reduction after single plasmapheresis therapy. However, there is paucity of data regarding the appropriate insulin dose and whether there is a linear dose-response in TG level reduction. Further studies are required to develop standard treatment guidelines for ASP-induced HTG which may help alleviate serious complications such as acute pancreatitis. Reference: Tozuka et al “Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma.” Annals of Clinical & Laboratory Science 1997

Abstract P2-09-14: A predictive model of pathological response following dual HER2 blockade-only based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer

Abstract Background: Increased number of tumor-infiltrating lymphocytes (TILs) at baseline is associated with pathological complete response (pCR) and improved outcomes in HER2-positive early breast cancer treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is currently unknown. Methods: The PAMELA (NCT01973660)neoadjuvant trial treated 151 women with HER2-positive breast cancer with lapatinib and trastuzumab (and hormonal therapy if hormone receptor-positive) for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (n=148) and after 2 weeks of treatment (n=134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated using univariate and multivariable logistic regression models. The regression coefficients were used to derive a score based on TILs and tumor cellularity measured at week 2 (CelTIL) was derived in PAMELA,and tested in week 2 samples from 65 patients with HER2+ disease recruited in the LPT109096 (NCT00524303) phase 2 neoadjuvant trial, where anti-HER2 therapy-only (trastuzumab, lapatinib or the combination) was administered for 2 weeks, followed by the addition of standard multi-agent chemotherapy for 24 weeks. Results: In PAMELA, at baseline, TILs were significantly associated with pCR in univariate analysis but not in multivariable analysis (adjusted odds ratio [OR]=1.01, 0.98-1.03; p-value=0.620). A statistically significant increase in TILs was observed at week 2 compared to baseline (mean difference +6.9%; p-value&amp;lt;0.001). At week 2, TILs were significantly associated with pCR in univariate and multivariable analyses (adjusted OR=1.04, 1.01-1.06; p-value=0.009). TILs and tumor cellularity at week 2 were independently associated with pCR and a combined score (from 0 to 100) taking into account both variables was derived. CelTIL as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores (cutoff &amp;lt; 33.59) had a pCR rate of 0% and 33%, respectively. Independent validation of CelTIL in week 2 samples from 65 patients with HER2+ disease recruited in the LPT109096 phase 2 neoadjuvant trial will be presented at the conference. Conclusions: A combined score of TILs and tumor cellularity at week 2 following anti-HER2 therapy-only is associated with pCR upon completion of neoadjuvant anti-HER2-based therapy. Citation Format: Nuciforo P, Holgado E, Llombart A, Fasani R, Paré L, Pascual T, Oliveira M, Martínez N, Bermejo B, Vidal M, Pernas S, López R, Muñoz M, Garau I, Manso L, Alarcón J, Martínez E, Villagrasa P, Cortés J, Prat A. A predictive model of pathological response following dual HER2 blockade-only based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-14.

T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy

Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy.Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines.Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance.Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506-15. ©2016 AACR.

Sensitivity of Medicare Claims Data for Measuring Use of Standard Multiagent Chemotherapy Regimens

We sought to determine the accuracy with which Medicare billing data documents elderly Medicare cancer patients' receipt of common multiagent chemotherapy regimens. We merged gold-standard clinical trial data from 406 elderly cancer patients known to be treated on 1 of 6 Cancer and Leukemia Group B (CALGB) breast, colorectal, and lung cancer trials (trial numbers; 9344, 9730, 9235,9732, 80203, 89803) with their Medicare claims data from Centers for Medicare and Medicaid Services (CMS). Comparing CMS chemotherapy codes to gold-standard CALGB treatment data, we estimated Medicare data's sensitivity at measuring the correct drugs and schedule for each of the multiagent chemotherapy regimens. Overall 92% (375/406) of CALGB patients had contemporaneous CMS claims indicating receipt of chemotherapy. The overall sensitivity of CMS ambulatory claims for documenting treatment with the correct drugs and on the correct schedule (ie, all drugs had to be billed on the same day) for the 5 common multiagent chemotherapy regimens was 78% (275/354) for those potentially treated in the ambulatory setting. The sensitivity was similar for all treatment regimens: carboplatin and paclitaxel 83%, 5-fluorouracil and leucovorin 80%, fluorouracil, leucovorin, and irinotecan (FOLFIRI) 76%, doxorubicin and cyclophosphamide 75%, and cisplatin and etoposide 75%. We correctly identified at least 3-quarters of elderly Medicare cancer patients treated on a clinical trial with standard first-line multiagent chemotherapy regimens in the ambulatory setting by applying coding algorithms to their CMS claims. The algorithms may be useful in identifying cohorts of elderly Medicare patients for observational studies of the comparative effectiveness of standard multiagent chemotherapy regimens.

A Phase I Study Of The Histone Deacetylase Inhibitor Entinostat Plus Clofarabine For Philadelphia Chromosome Negative, Poor Risk (Newly Diagnosed Older Adults or Adults with Relapsed and Refractory Disease) Acute Lymphoblastic Leukemia Or Bilineage/Biphenotypic Leukemia

Abstract Introduction Adult patients (pts) diagnosed with acute lymphocytic leukemia (ALL) are known to have a poor clinical outcome as compared to children. Studies report a 2 year event free survival of 30-40% for Philadelphia chromosome negative (Ph-) patients age &gt;30 yrs and 17% for age &gt;50 yrs. In order to improve outcome for adult ALL, agents that are effective, safe and associated with a low morbidity are needed. Clofarabine, a second generation purine nucleoside analog, has clinical activity as a single agent and in combination with cytosine arabinoside (ara-C) against refractory and relapsed ALL. Clofarabine exerts its cytotoxicity through multiple mechanisms of action, with major effects via inhibition of ribonucleotide reductase (RR) and DNA polymerase-alpha, and incorporation into DNA leading to DNA damage and activation of apoptotic pathways. Histone deacetylases (HDACs) are important regulators of chromatin involved in silencing of tumor suppressor genes. HDAC inhibitors are shown to be apoptogenic in vitro for ALL cell lines and have received FDA approval for the treatment of CTCL and peripheral T cell lymphoma. Pre-treatment with entinostat has been shown to enhance the cytotoxic activity of fludarabine in leukemia cell lines in vitro (Maggio et al, Cancer Research 2004). Given the similarity of clofarabine to fludarabine, and its FDA approval for children with refractory ALL, the combination of entinostat with clofarabine was pursued. Methods A Phase I window of opportunity study using overlapping schedule of entinostat and clofarabine was used in adult pts with ALL (B precursor) or Acute Bilineage Leukemia (ABL). Pts were enrolled onto one of two arms; arm “A” received repeated cycles of entinostat-clofarabine every 21 days as long as there was evidence of response (CR, CRi, or PR following cycle 1) and pts on arm “B” received one cycle of entinostat-clofarabine prior to standard multi-agent chemotherapy. Entinostat was administered orally on day 1 and day 8 (with dose escalation from flat dosing of 4mg to 6mg to 8mg from cohort 1 to 3). Clofarabine was administered intravenously at a fixed dose for all dose cohorts at 10mg/m2 for 5 days (day 3-7). Adults &gt;40 yrs with newly diagnosed, Ph- B-lineage ALL or ABL were eligible. Additionally, adults &gt; 21 yrs with relapsed and refractory, Ph- ALL or ABL were eligible. Eligibility criteria included serum creatinine &lt; 2.0 mg/dl, hepatic enzymes &lt; or = 2.5 ULN and bilirubin &lt;2.0 mg/dl. WBC &lt;150,000/mm3 with no evidence for ongoing or impending leukostasis was required. Results 23 pts from 3 institutions were enrolled on this study (18 at JHH, 3 at UMD, 2 at UColorado). 17 pts were treated on arm A and 6 pts on arm B. 6 pts were treated in each dose level with responses as follows: in dose level one (1 CR, 5 NR) and dose level two (1 CR, 1 CRi, 4NR) and dose level three (3 PR and 3 NR). The dose level 3 cohort was expanded with a total of 5 additional pts to date (1 PR, 1 SD, 3NR). Thus, the overall response rate on dose level 3 was 4PR, 1SD, 6NR. The 4 pts with CR/CRi/PR were all de novo treated elderly pts from Arm A. Notably, one pt on arm A has been in remission for over 1.5 yrs. Toxicities to date included expected but manageable grade (G) 3 and 4 cytopenias. There were G3 elevations of ALT (N=2) and AST (2) and bilirubin (1) and one bacteremia (1) and G4 cellulitis (1). Planned correlative studies are ongoing and include evaluation of acetylation of target proteins using multiparameter flow cytometry and western blot as well as methylation evaluation. Conclusions Combination therapy with entinostat-clofarabine is feasible and is well tolerated with minimal toxicity. Promising durable responses were observed in older pts that were not otherwise able to receive multi-agent induction chemotherapy upfront. This is notable given the low dose of clofarabine used in every cohort. Correlative studies evaluating protein hyperacetylation and DNA methylation in serial samples from treated pts are in progress. Disclosures: Off Label Use: This clinical study is a Phase 1 investigation and it discusses non-FDA approved doses of both clofarabine and entinostat for adults with Acute Lymphocytic Leukemia. The reason for this is that this study examines these agents in combination in a Phase 1 fashion and we started with low doses of each agent. Ordentlich:Syndax: Employment. Trepel:Syndax: Research Funding.

It's ALL in the Liposomes: Vincristine Gets a New Package

It's ALL in the Liposomes: Vincristine Gets a New Package

A pilot study of low‐dose anti‐angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children's Oncology Group (COG) Phase II study NCT00061893

The aims of this study were to determine the feasibility of the combination of low dose, anti-angiogenic chemotherapy with standard therapy for patients with metastatic Ewing sarcoma (ES), and to obtain preliminary outcome data. Patients with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide-etoposide, and vincristine, doxorubicin, cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference. Thirty-five eligible patients were enrolled. Ninety percent received at least 75% of planned vinblastine/celecoxib doses. There was no excess of neurologic, infectious, hemorrhagic, or cardiovascular toxicities. However, 7 of 21 patients who received pulmonary irradiation prior to experiencing pulmonary toxicity did develop grade 2 or greater pulmonary toxicity, including two deaths of apparent radiation pneumonitis. Fourteen of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19-51%); 71% (26-92%) for the seven with isolated pulmonary metastases, 26% (10-45%) for all others. The combination of vinblastine/celecoxib metronomic therapy with standard ES treatment was feasible according to the protocol definitions. However, excess toxicity in irradiated areas was noted and limits the usefulness of this protocol. The 24-month EFS for those with isolated pulmonary metastases is better than historical controls, although the number of patient number is small, follow up short and we are lacking contemporaneous controls.

A multidisciplinary treatment comprising standard chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for Ewing sarcoma family of tumor (ESFT) in Japan: Results of the first Japan Ewing Sarcoma Study (JESS) 04.

9574 Background: Survival rate of ESFT in Japan was reportedly less than 50% in 1990s. The JESS started in order to improve this condition by conducting clinical trials for ESFT in Japan. Methods: This is a phase II, non-randomized trial to test safety and efficacy of multidisciplinary treatment for non-metastatic ESFT. Age under 30 is eligible. Chemotherapy regimens are alternating vincristine 1.5 mg/m2 on day 1, doxorubicin 37.5 mg/m2 on days 1 and 2, cyclophosphamide 1200 mg/m2 on day 1 (VDC) and ifosfamide 1800 mg/m2 on days 1 through 5 and etoposide 100 mg/m2 on days 1 through 5 (IE) repeating every 21 days for 52 weeks. Local treatment includes surgical resection and/or radiation therapy, of which dosage varies from 0 to 55.8 Gy based on margin of the resection and pathological response. Primary endpoint is 3 year progression free survival (PFS). Statistical design was made to test whether the lower limit of 90% confidence interval (CI) of PFS will exceed the threshold of 60%. Planned sample size is 53 patients including 10% ineligible patients. Results: Fifty-three patients were registered from December 2004 to May 2008. Among the 53 patients, 7 patients were judged ineligible after the registration (metastatic disease 1, changed diagnoses 6). Forty six patients were considered as per protocol set and used for efficacy analyses. Three year PFS is 71.7% (90% CI: 0.59 – 0.81). Estimated 5 year PFS and OS are both 69.6%. Radiographic response rate (RR) in evaluable 38 patients is 71.1% and pathological RR in 25 is 52.0%. In safety data, hematological toxicities are significant such as grade 4 neutropenia observed in 98%. Although there is no previously unknown adverse event reported, there are three patients who experienced secondary malignancies (ALL 1, MDS 1, osteosarcoma 1). Conclusions: A multi-disciplinary treatment comprising standard multi-agent chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide improved outcome of Ewing sarcoma family of tumor in Japan although statistical confirmation of absolute efficacy was not successful.

Clinical analysis of 15 cases of malignant ovarian germ cell tumors with lung metastasis

To investigate the clinical characteristics, diagnosis, treatment and prognosis of malignant ovarian germ cell tumors (MOGCT) with lung metastasis. Fifteen patients of MOGCT with lung metastasis treated in Peking Union Medical College Hospital from Jan. 1982 to Dec. 2010 was retrospectively analyzed. (1) Clinical characteristics: the average onset age of these 15 patients is (23 ± 11) years old (6 - 48 years). The majority of these patients presented with abdominal pain (8/15) or irregular vaginal bleeding (4/15) as their initial symptoms. The primary tumor located in the left ovary in 8 cases, right ovary in 6 cases, and both sides in only 1 case. Metastatic lesions were confined to the lung in 12 patients, while the other 3 patients were found to have multi-site distant metastasis. (2) DIAGNOSIS:all 15 cases included 9 pure non-gestational ovarian choriocarcinoma (NGOC), 3 MOGCT containing choriocarcinoma component (one mature teratoma with choriocarcinoma component, one endodermal sinus tumor with embryonal carcinoma and choriocarcinoma components, one choriocarcinoma with dysgerminoma component), 2 embryonal carcinoma, one immature teratoma. Only one patient in these 15 cases was correctly diagnosed before surgery. (3) Time of lung metastasis:of 12 MOGCT with choriocarcinoma component, 11 patients were found to have lung metastasis in the course of their primary treatment, only 1 had lung metastasis 2 months after the synthetic treatment finished. Three MOGCT patients without choriocarcinoma component were all found to have lung metastasis when tumor relapsed in the advanced stages of the disease. (4) TREATMENT:all 15 patients received multi-agent chemotherapy combined with surgery. The mean courses of chemotherapy for these patients were 16 courses (5 - 43 courses). (5) PROGNOSIS: of these 15 cases, complete remission was obtained in 10 patients of NGOC or mixed ovarian germ cell tumors with choriocarcinoma component, 3 patients (one NGOC, one endodermal carcinoma and one immature teratoma, respectively) died in the course of treatment as result of tumor progression, 2 progressed cases (one NGOC and one endodermal carcinoma respectively) abandoning therapy were lost to follow up. MOGCT with lung metastasis are more often to found in NGOC patients. These patients could obtain high complete remission rate after standard multi-agent chemotherapy combined with surgery. The prognosis of MOGCT with lung metastasis containing choriocarcinoma component are better than that of those without containing choriocarcinoma component.

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

Neuropsychological Outcomes of Older Breast Cancer Survivors: Cognitive Features Ten or More Years After Chemotherapy

The authors examined the long-term cognitive implications of cancer treatment among breast cancer survivors over 65 years old who received treatment during midlife. Thirty women survivors were matched with 30 noncancer, healthy older adults in terms of age, education, and IQ. The cancer survivors scored significantly lower in the cognitive domains of executive functioning, working memory, and divided attention, reflecting potential dysfunction in frontal-subcortical brain regions. Our findings suggest that among breast cancer survivors who remain disease-free for more than a decade, the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes.

Molecular Signatures to Improve Diagnosis, Prognostication and Identification of Oncogenic Pathways in Peripheral T and NK Cell Lymphoma.

Background: Peripheral T-cell lymphoma (PTCL) consists of an uncommon and heterogeneous group of lymphomas that are often challenging to diagnose and classify. Since most patients also have a poor survival with standard multiagent chemotherapy, more effective therapeutic approaches are needed to improve patient outcome.Table1:Pathological diagnosisNumber of cases profiledAITL36ALK(+)ALCL19ALK (−)ALCL08ATLL12T/NK14PTCLU44Other rare entities10Methods: A mRNA profiling study using Affymetrix HGU133+2 arrays on 143 cases of PTCL and NK-cell lymphoma (NKCL) from the International Peripheral T-cell Lymphoma Project, was conducted on pre-treatment biopsies. These included the following pathologically classified cases (Table 1). In addition, we also profiled nine NK cell lines, seven T cell lines, normal resting and activated CD4+ and CD8+ T cells and resting and IL2- activated NK cells from healthy individuals. BRB-ArrayTools was used to develop gene classifiers for the major PTCL entities and survival predictors for AITL based on gene expression data.Results: We have identified key molecular signatures for PTCL and NKCL that have allowed us to construct a robust classifier for AITL (207 transcripts), ALK+ ALCL (94), ATLL (225) and NKCL (127). PTCL-U group may have 3 or 4 molecular subgroups and additional studies with more cases, are necessary to further define this group. Misclassified cases were identified and re-assigned to the molecularly defined entities, including re-assigning of 9/44 PTCL-U to AITL. We have confirmed the enriched expression of genes identified in follicular helper T-cells in AITL, suggesting that AITL is derived from this T-cell subset. A number of oncogenic pathways (e.g. NF-κB, HIF-a,VEGF, IL6) and tumor/host interactions that contributed to local tumor-induced immunosuppression (e.g. TGF-b), were identified in AITL. A molecular predictor of outcome was developed for AITL and validated by leave one-out-cross validation. Since PTCL is an uncommon disease, future studies will require the collaboration of multiple large clinical groups with tissue resources for both discovery and validation.Conclusion: This study has demonstrated that GEP will allow the construction of robust and biologically-meaningful classifiers for PTCL, and prognosticators can be derived for well-defined entities with a sufficient number of cases. GEP will also allow us to identify therapeutically-relevant oncogenic pathways and tumor/host interactions that may lead to improvement in the therapy and outcome of patients with PTCL and NKCL. (This study is a part of the International T-cell Lymphoma Project)

Randomized phase II window study of two schedules of irinotecan (CPT-11) and vincristine (VCR) in rhabdomyosarcoma (RMS) at first relapse/disease progression

10013 Background: Patients with RMS have a poor prognosis at first relapse/disease progression. CPT-11 has significant and schedule-dependent preclinical activity in RMS, and prolonged exposure results in increased efficacy. Methods: Patients with biopsy proven RMS, < 21 years of age at original diagnosis and unfavorable prognosis at first relapse/progression were eligible. Entry criteria were: life expectancy ≥ 2 months, performance status ≤ 2, adequate organ function and written informed consent. Patients were randomized to one of two schedules of CPT-11/VCR: Regimen 1A: CPT-11, 20 mg/m2 intravenously (IV) daily × 5d × 2w on weeks 1 and 4, VCR 1.5 mg/m2 IV on day 1 of weeks 1, 2, 4 and 5; Regimen 1B: CPT-11, 50 mg/m2 IV daily × 5d on weeks 1 and 4, VCR identical to IA. Disease response at week 6 was assessed using RECIST. Secondary endpoints included toxicity, progression free survival (PFS) and survival (OS). The study was powered to detect a 25% improvement in response to IA when compared to IB (α=0.1, 1-β=0.9, 1-sided test). Those with responsive/stable disease continued to receive 44 weeks of standard multi-agent chemotherapy (doxorubicin, cyclophosphamide, etoposide, ifosfamide) in combination with their assigned CPT- 11/VCR regimen. Results: 92 patients were randomized (IA-45, IB-47). Response in 86 evaluable patients was: 1A - 4 CR, 6 PR, 11 SD, 19 PD (overall response 25%) 1B - 0 CR, 17 PR, 14 SD, 15 PD (overall response 37%) (p=0.23). The 1-year PFS on IA was 32% (95% CI: 18%, 47%) and for IB was 36% (95% CI: 22%, 50%). The 1-year OS for IA was 47% (95% CI: 30%, 62%) and 1B was 56% (95% CI: 40%, 69%). There were no unexpected toxicities or significant differences in toxicity between the two regimens. Conclusions: There was no difference in the response rates between the two CPT-11/VCR regimens. The shorter, more convenient CPT-11/VCR regimen is now being investigated in frontline Children’s Oncology Group RMS clinical trials. No significant financial relationships to disclose.

State-of-the-Art Therapeutics: Hodgkin's Lymphoma

Presently Hodgkin's lymphoma can be cured in at least 80% of patients. The major challenge to the clinician in 2005 is how to cure the disease while inducing the least irreversible toxicity. This review focuses on clinical trials and institutional experiences to identify the best choice of treatment, individualized to the stage of the lymphoma permitting minimization of late toxicity such as infertility, premature menopause, cardiac disease, and most importantly, risk of second neoplasms. More than 90% of patients with limited Hodgkin's lymphoma can be cured with either short-course chemotherapy alone or even briefer chemotherapy followed by involved-field radiation. Accumulating evidence suggests that chemotherapy alone is suitable for the large majority of patients with limited disease. For the 80% of patients with advanced disease but without a large number of adverse prognostic factors, standard multi-agent chemotherapy with the well-established ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) provides the best balance of effectiveness and minimization of toxicity. More intensified regimens currently under investigation are appropriate for the 20% with numerous adverse prognostic factors. In 2005 it is insufficient to focus solely on cure of Hodgkin's lymphoma. The treatment program must maximize chance of cure and minimize late toxicity. Fortunately, brief chemotherapy alone or with radiation for patients with limited disease and standard ABVD chemotherapy for patients with advanced disease offer the appropriate balance of these two requirements. Patients with advanced disease plus multiple indicators of a poor prognosis and patients with disease that persists despite optimized primary treatment require specially intensified treatment.

Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide.

Standard multiagent chemotherapy for osteosarcoma may include platinum compounds, doxorubicin, and high-dose methotrexate. By identifying new chemotherapeutic strategies, the outcome of these patients can be improved and the toxicity of treatment regimens decreased. The authors evaluated the activity of the combination of cyclophosphamide (500 mg/m2 per day for 5 days) and etoposide (100 mg/m2 per day for 5 days) given with granulocyte colony-stimulating factor (G-CSF) to children with osteosarcoma unresponsive to conventional treatment. Fourteen patients with refractory osteosarcoma were treated with this combination. Twelve patients had been previously treated with a multiagent regimen that included carboplatin, ifosfamide, methotrexate, and doxorubicin. Seven of 11 evaluable patients had a poor histologic response in their primary tumor at the time of definitive surgery (Huvos grade 1 or 2). Sites of relapse included lung, bone, and brain. A total of 47 courses were given. An overall response rate of 28.5% was achieved. A complete response was obtained in one patient (7.1%), a partial response was obtained in three patients (21.4%), and stable disease for 1 to 4 months was achieved in five patients (35.7%). Five patients (35.7%) had progressive disease. Grade 4 neutropenia was the primary form of toxicity observed; the median duration of absolute neurophil count less than 500/microL was 4 days. The combination of cyclophosphamide and etoposide resulted in a response rate of 28.5% in patients with refractory or relapsed osteosarcoma, and its incorporation into front-line therapies deserves further evaluation.