Dose Escalation Of Chemotherapy Research Articles

GCT-08. THE PURSUIT OF OPTIMUM TREATMENT FOR NONGERMINOMATOUS GERM CELL TUMOURS (NGGCT) OF THE CNS – A PROGRESS REPORT FROM THE EUROPEAN GROUP (SIOP CNS GCT II)

Abstract BACKGROUND Controversy surrounds the optimum treatment for localised nongerminomatous germ-cell-tumours (NGGCT). The European group has employed more dose-intense chemotherapy followed by 54 Gy focal radiotherapy (fRT), whilst others additionally apply whole-ventricular or craniospinal radiotherapy (CSI). Historically, these approaches have led to comparable outcomes. PATIENTS/METHODS SIOP-CNS-GCT-II aimed to improve event free survival (EFS) for NGGCT by standardising the surgical approach for residual disease and by chemotherapy dose escalation in patients identified as high-risk (age <6 years and/or serum/CSF AFP >1000 ng/ml). Standard treatment with four courses of cisplatin, etoposide and ifosfamide (PEI) followed by 54 Gy fRT with 30 Gy CSI for metastatic disease, was retained from the SIOP-CNS-GCT-96 trial for patients not defined as high-risk. Radiotherapy technique (protons or photons) was not dictated in the trial, but the number of cases receiving proton beam therapy has increased over time. Between 02/2012 and 07/2018, 112 patients with NGGCT from eight European countries were treated according to the SIOP-CNS-GCT-II protocol; 89 were standard-risk, and 14 of these were metastatic. This compared with 149 NGGCT patients treated overall in SIOP-CNS-GCT-96, of which 33 were metastatic. RESULTS In SIOP-CNS-GCT-96, 3-year EFS for localised NGGCT receiving PEI chemotherapy and 54 Gy fRT was 0.72, and for metastatic cases, receiving PEI and 30 Gy CSI with boost, 0.68. In SIOP-CNS-GCT-II, 3-year EFS for metastatic cases receiving similar treatment was excellent at 0.94 (p=0.087 compared with SIOP-CNS-GCT-96) but for localised cases, only 0.63 (p=0.032). CONCLUSION To understand the impact of radiotherapy volumes on EFS and guide future trials, a detailed dosimetric study on the patterns of relapses is in progress. In the meantime, based on our current understanding, most participating countries are recommending addition of whole ventricular radiotherapy to fRT for localised NGGCT.

Mature B-cell lymphomas in adolescents and young adults.

Pediatric non-Hodgkin lymphoma includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the US, compared to>60,000 cases of adult NHL annually. Improvements in survival in pediatric and adolescent mature B cell NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes through dose escalation of chemotherapy and, more recently, targeted therapy with rituximab. Pediatric dose-intense strategies carry risks of long-term consequences, but treatment failure is nearly universally fatal. By comparison, adult mature B cell lymphoma is typically less aggressive and treated with less intense chemotherapy. Optimizing therapy for adolescents and young adults remains a major challenge that requires creative solutions, including engineering study groups to combine biologically comparable adult and pediatric populations and developing effective salvage strategies that will ultimately be required for investigations of front-line dose reduction. In this review, we discuss challenges and opportunities for improving outcomes for adolescents and young adults with high-grade mature B cell lymphomas, diffuse large B cell lymphoma, and primary mediastinal B cell lymphoma.

A multi-center analysis of the impact of DA-EPOCH-R dose-adjustment on clinical outcomes of patients with double/triple-hit lymphoma

Patients with double- and triple-hit lymphomas (DHL/THL) have inferior outcomes with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and higher-intensity regimens such as dose-adjusted (DA)-EPOCH-R are standard. Dose-intensification of DA-EPOCH-R is guided by hematologic toxicity, without conclusive benefit for DHL/THL patients. To determine if cumulative doses of DA-EPOCH-R or compliance with dose adjustment impacts survival, we retrospectively evaluated detailed clinical data from 109 adult (age ≥18 years) patients with DHL/THL treated with ≥4 cycles of induction DA-EPOCH-R from 2014 to 2019 at six centers. A comprehensive multivariate analysis was performed. Survival outcomes for the entire cohort were comparable to historical estimates for DHL/THL treated with this regimen (median follow-up 27.9 months). Overall survival (OS) and progression-free survival (PFS) were not significantly associated with cumulative chemotherapy dose, dose escalation, or compliance with dose adjustment. Heterogeneous dosing practices were observed. Prospective investigation is warranted to evaluate the practice of dose adjustment of R-EPOCH for patients with DHL/THL.

MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial

Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation. We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m2) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m2) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m2). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS). Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m2) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively. Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.

Declining use of inguinofemoral lymphadenectomy in the treatment of clinically negative, pathologic node positive vulvar cancer

PurposeThe management of vulvar cancer with clinically negative groin lymph nodes but with positive sentinel lymph node biopsy (SLNB) is controversial, with options including inguinofemoral lymphadenectomy (IFL) and/or adjuvant chemotherapy and radiotherapy. We used the National Cancer Database (NCDB) to examine trends in the management of clinically node negative, pathologically node positive (cN-/pN+) patients. MethodsThe NCDB was used to identify cN-/pN+ vulvar cancer patients. Demographic and clinical data were compared with chi-squared and Wilcoxon rank-sum tests. OS was analyzed with the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to determine factors associated with OS. ResultsA total of 885 cN-/pN+ vulvar cancer patients were identified between 2012 and 2016, during which the rate of SLNB alone increased from 3.6% to 11.7%, while the rate of IFL +/− SLNB decreased from 89.7% to 78.1% (p < 0.05). Radiation was used in 68.5% and 64.6% of the SLNB-alone and IFL +/− SLNB cohorts, respectively, with chemoradiation in 37.1% and 33.6%, respectively. OS was not different between patients who received SLNB-alone vs. IFL +/− SLNB (p = 0.644). Receipt of chemotherapy and radiation was associated with improved OS (p < 0.001). ConclusionsAmong cN-/pN+ vulvar cancer patients in the NCDB, the practice of performing IFL decreased over time as SLNB-alone became more common and the majority received radiation +/− chemotherapy. There was no difference in OS between SLNB-alone vs. IFL +/− SLNB. Patients treated with adjuvant chemoradiation had improved survival. Whether the favorable outcomes in the SLNB-alone cohort may be attributed to radiotherapy dose escalation or use of chemotherapy warrants further study.

Radiation to the Primary Tumor in Metastatic Anaplastic Thyroid Cancer.

Metastatic anaplastic thyroid cancer is associated with a dismal prognosis. We evaluated outcome and prognostic factors in patients receiving radiation to the primary tumor in metastatic anaplastic thyroid cancer (ATC). All consecutive patients with metastatic ATC (n=20) undergoing irradiation between 2009 and 2019 for anaplastic thyroid cancer were investigated. Median survival time and median progression-free survival were 2 (range=1-22) and 2 (1-20) months. In univariate analyses, surgery, concurrent or sequential chemotherapy and higher radiation dose escalation (>39 Gy) were correlated with longer overall survival (p=0.005, p=0.018 and p=0.038), respectively. Karnofsky performance status >70% showed a trend of longer survival time (p=0.062). Limited metastatic disease, surgery and concurrent/sequential chemotherapy are correlated with longer progression-free survival times (p=0.043, p=0.024 and p=0.039), respectively. Radiation to the primary tumor in metastatic anaplastic thyroid cancer is safe and offers durable local control. Treatment intensification including concurrent or sequential chemotherapy and radiation dose escalation were associated with longer survival rates and should be considered in selected patients with metastatic disease.

An Aggressive Approach To An Aggressive Tumor – Role Of Multimodality Treatment In Brainstem Glioma

Brain Stem Glioma constitutes 1% to 2% of adult and 10% of pediatric gliomas. Unlike the gliomas in other sites of CNS, brainstems are not amenable for surgery for most of the cases, making radiotherapy a viable treatment option. The median overall survival with conventional fractionated radiotherapy is approximately 10 months. Historical studies done on dose escalation in terms of hypofractionation did not prove any survival benefit. Addition of radiosensitizers did not give an edge over survival, with a median OS of 11.5months. With advances in radiation delivery, efforts have been made to deliver higher dose to the tumor and reducing normal tissue toxicity. We combined both dose escalation and chemotherapy with an intent to improve local control and survival outcomes with acceptable level of toxicities. We recruited 50 patients of Brain Stem Glioma between June 2009 to Dec 2019. All patients underwent DOPA PET and MRI based planning and were treated in 2 phases. Phase 1 was conformal EBRT to a dose of 44Gy in 22 fractions to the volume correlating PET and MR, 39.6Gy in 22 fractions to CTV (1cm expansion from GTV) over 5 weeks. Phase 2 included re-planning with DOPA and MRI based HFSRS boost to residual disease as correlated with PET/MR to a dose 10-12Gy in 2 fractions, to a total BED of 72Gy. All patients received concurrent Temozolomide daily for 45 days throughout the treatment, followed by adjuvant temozolomide of 6-12 cycles. Assessment was done with DOPA/MET PET and MRI every 3 months for 1 year, every 6 months for 2 year and annually thereafter. Overall survival rates were analyzed at the end of 1, 2 and 3 years. In the current sample of 50 patients (19 were pediatric, 31 adults, M:F – 32:18). Age range was 2-73yrs with a median of 27 yrs. The median overall survival was estimated to be 36months CI [3.492-68.51]. The 1-year, 2-year and 3-year survival rate for this group was 61.51%, 56.59% and 40.42% respectively. From our study we conclude that dose escalation and addition of chemotherapy can be considered as a safe and effective treatment in patients with brainstem glioma, with increase in survival as compared to existing literature with acceptable level of toxicities and better preservation of neurological function.

Treatment results of pediatric acute myeloid leukemia with epigenetic drugs addition

Background. Currently, overall survival rate for pediatric patients with acute myeloid leukemia (AML) do not exceed 70 %. The intensity of modern AML chemotherapeutic programs has reached its limit, and further chemotherapy dose escalation for treatment results improvement is impossible, because it fraught with life-threatening complications. It is investigating a new ways of tumor treatment for improvement of AML patient’s survival level: therapeutic efficacy of targeted and epigenetic drugs.Objective: to evaluate the efficacy of epigenetic drugs (azacitidine, decitabine, all-trans-retinoid acid and valproic acid) in combination with AML-BFM 2004 protocol for treatment of pediatric AML.Materials and methods. 80 patients with primary AML diagnosis were enrolled the study. Age was ranged from 8 months to 17 years (median 6.7 ± 0.6 years). From June 2012 to January 2018 all patients were subdivided in two treatment groups. 1st group included 34 patients treated with NII POH AML 2012 protocol, 2nd group – 46 patients treated by AML-BFM 2004 protocol.Results. 3-year relapse-free survival in 1st group, regardless of prognostic risk group, was 66.7 ± 11.7 %, 2nd group – 68.9 ± 9.9 %. Eventfree survival (EFS) for patients from 1st group was 66.7 ± 11.7 %, form 2nd group – 50.4 ± 10.2 %. Overall survival in 1st group was 66.7 ± 14.3 %, 2nd group – 66.9 ± 7.5 %. For patients with unfavorable risk from 1st treatment group 3-year relapse-free survival was 69.1 ± 11.9 %, 2nd – 64.9 ± 11.3 % (p = 0,8). EFS – 69.1 ± 11.9 and 44.8 ± 11.3 % respectively (p = 0,13). 3-year overall survival for patients with unfavorable risk group was 69.4 ± 14.6 and 64.4 ± 7.9 % in 1st and 2nd treatment groups respectively.Conclusion. The efficacy of decitabine in “window” regimen was higher in contrast to azacitidine; epigenetic therapy with AML-BFM 2004 protocol allow us to achieve a higher EFS, because of induction mortality and infection-related death decrease – EFS in 1st group was 16 % higher than in 2nd. Besides, EFS in unfavorable risk group, who treated with epigenetic drugs, was 25 % higher – 69.1 ± 11.9 % and 44.8 ± 11.3 % in 1st and 2nd groups respectively (p = 0.13). Nevertheless, overall survival in both groups was the same – 66 % (1st – 66.7 ± 14.3 % and 2nd – 66.9 ± 7.5 %).

Therapeutic Effect of Chemotherapy Cycle in Nasopharyngeal Carcinoma (NPC) Patients Who Developed Bone-Only Metastasis.

BackgroundTo compare the effects of chemotherapy dose escalation on survival and prognosis of nasopharyngeal carcinoma (NPC) patients who developed bone-only metastasis.Material/MethodsBetween October 2000 to March 2017, 58 NPC patients with initial bone-only metastasis were retrospectively analyzed. Patients who received <6 or ≥6 cycles of chemotherapy were matched and grouped using receiver operating characteristic curve (ROC) analysis. Overall survival (OS) was assessed using the Kaplan-Meier method, log-rank test, and Cox regression analysis.ResultsThe median OS for the entire group was 24 months, while the 1-, 2-, and 3-year OS rates were 78.5%, 49.4%, and 26.8%, respectively. The median OS for patients who received <6 cycles of chemotherapy was 21 months, with 1-, 2-, and 3-year OS rates of 64.8%, 34.3%, and 17.2%, respectively. The median OS of patients who received ≥6 cycles of chemotherapy was 26 months, with 1-, 2-, and 3-year OS rates of 92.6%, 54.9%, and 30.9%, respectively. Multivariate analysis showed that the number of metastatic sites (≥3 vs. <3) and chemotherapy cycles (<6 vs. ≥6) were independent prognostic factors for OS.ConclusionsNPC patients who had less than 3 bone metastatic sites and who received ≥6 cycles of chemotherapy had better survival and prognosis.

Unintended Consequences of Treating Early Rectal Cancers for Complete Clinical Response with Chemoradiotherapy

The aim was to examine the current trend in rectal cancer, which is to extend ’watch-and-wait’ to earlier-stage tumors, not normally treated with chemoradiotherapy, to define the up-side and down-side regarding quality of life (QOL) and anorectal/sexual/urinary function from this approach. We reviewed the literature regarding a ‘watch-and-wait’ strategy after neoadjuvant chemoradiotherapy. The primary outcome measure was complete clinical response. Secondary measures included colostomy rate, functional outcomes and QOL. There is a trend to use chemoradiotherapy in earlier tumors using dose-escalation of radiation and/or additional chemotherapy, resulting in high rates of complete clinical response, which may impact adversely on QOL if radical surgery is subsequently required. Focusing on organ-preservation as the primary goal of treatment rather than overall functional outcomes and QOL for the whole population, may not provide patients with sufficient information for optimal decision-making.

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

A phase I dose-escalation of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) carboplatin for the frontline treatment of advanced ovarian cancer.

5554Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of frontline ovarian cancer surgery has shown preliminary overall survival benefit, but selection of chemotherapy agent...

Tandem High-dose Chemotherapy and Autologous Stem Cell Transplantation in Children with Brain Tumors : Review of Single Center Experience.

The prognosis of brain tumors in children has improved for last a few decades. However, the prognosis remains dismal in patients with recurrent brain tumors. The outcome for infants and young children in whom the use of radiotherapy (RT) is very limited because of unacceptable long-term adverse effect of RT remains poor. The prognosis is also not satisfactory when a large residual tumor remains after surgery or when leptomeningeal seeding is present at diagnosis. In this context, a strategy using high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) has been explored to improve the prognosis of recurrent or high-risk brain tumors. This strategy is based on the hypothesis that chemotherapy dose escalation might result in improvement in survival rates. Recently, the efficacy of tandem HDCT/auto-SCT has been evaluated in further improving the outcome. This strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates. At present, the number of studies employing tandem HDCT/auto-SCT for brain tumors is limited. However, results of these pilot studies suggest that tandem HDCT/auto-SCT may further improve the outcome. In this review, we will summarize our single center experience with tandem HDCT/auto-SCT for recurrent or high-risk brain tumors.

Prospective Phase I Multi-Center Trial Incorporating Lenalidomide (LEN) into Dose-Adjusted EPOCH Plus Rituximab (DA-EPOCH-R) in Patients with Double Hit (DHL) or Double Expressing (DEL) Lymphomas: Final Results

Background: There are no prospective studies that define best therapy for DHL (presence of c-MYC and BCL-2 translocations) or DEL (co-expression of c-MYC ³40% and BCL-2 ³50% by IHC). Retrospective data for both entities show suboptimal outcomes with R-CHOP and perhaps improved outcomes with intensified regimens such as DA-EPOCH-R. We conducted a phase I prospective multicenter study adding escalating doses of LEN to DA-EPOCH-R in pts with DHL or DEL. Herein, we report the final results of the dose-finding portion of this ongoing clinical trial.Patients and Methods: Eligible pts had DHL or DEL as defined above. They were allowed to receive radiotherapy for neurologic compromise or one cycle of R-CHOP prior to enrollment at the investigator's discretion. Pts had measurable disease, ECOG PS 0-2, and adequate liver, kidney, and marrow function and no known HIV or CNS involvement. Either aspirin or warfarin prophylaxis was required. Primary objective was to determine the maximum-tolerated dose (MTD) of LEN when added to DA-EPOCH-R. We utilized a standard (3+3 design) where LEN was started at 10mg (days 1-14, Q21-days) with each cycle of DA-EPOCH-R, and escalated to a maximum of 25 mg unless a MTD was reached at an earlier dose. Dose-limiting toxicities (DLTs) were assessed during cycle 1; DA-EPOCH-R administration and dose modifications were conducted as per usual protocol. Cycles were repeated every 3-weeks for a maximum of 6 cycles and were followed by an end of therapy PET scan. CNS prophylaxis was strongly encouraged with 12.5 mg IT-methotrexate for 4 doses during induction. Patients attaining PET negativity after induction were continued on maintenance LEN 10 mg (days 1-14 Q21 days) for 12 cycles. During the LEN dose escalation portion of the study, a hematologic toxicity did not count as a DLT to allow DA-EPOCH-R dose adjustments.Results: 15 pts (6: DHL and 9: DEL; 13 DLBCL and 2 BCL-U) were enrolled; median age was 62 years (range: 26-83). There were 5 males and 10 females (11 whites, 3 African Americans, and 1 Asian pts). Two pts had ECOG PS 2 while all others were 0-1. All pts (100%) had stage III/IV disease, 13 pts (86%) had high-risk IPI score, and median LDH was 673 (range: 193-1,835). All ptsare assessable for toxicity. Serious adverse events (SAEs) per dose levels are summarized in the Table. DA-EPOCH-R dose escalation was feasible in 10 pts (67%), one pt (6.7%) maintained the same dose throughout, and another (6.7%) required dose de-escalation. Two DLTs were observed (grade 4 sepsis and hypotension for both) at dose-level 20 mg of LEN leading to 15 mg being the MTD and RP2D. Most common grade 1 and/or 2 non-hematologic toxicities were fatigue (70%), constipation (47%), alopecia (53%), nausea (47%), peripheral sensory neuropathy (40%), diarrhea (33%), and hypokalemia (33%). The only grade 3 and/or 4 non-hematologic toxicity occurring in ³2 pts (13%) was hypokalemia. All others occurred in 1 pt (6%) and were: constipation, fever, hyperglycemia, hypertension, mucositis, and hypoalbumenemia. One pt (6%) developed treatment-related myelodysplasia, (T-MDS), 18 months after treatment initiation. Twelve patients are evaluable for response at time of analysis, (1 patient lost to follow-up, and 2 with ongoing therapy). Best responses at completion of induction based on PET were 6 complete responses (CR: 50%), 3 partial responses (PR: 25%) and 1 pt with progressive disease (8%). All CR pts received LEN maintenance but only 1 completed 12 cycles to date (1 came off due to cytopenias found later to have T-MDS, 1 due to AE, 1 due to finding of unrelated colon cancer, 2 on active maintenance). With median follow up 10.7 months (range: 1.3-18.6 months), 14 pts remain alive and one pt has died for an OS of 93%.Conclusions: LEN can safely be added to DA-EPOCH-R in DHL and DEL patients at a dose of 15 mg (days 1-14 Q21 days). Chemotherapy dose escalation was not compromised and preliminary safety/efficacy data appear promising. A phase II study in this pt population with LEN+DA-EPOCH-R is underway. [Display omitted] DisclosuresNabhan:Celgene, Genentech, Seattle Genetics, Astellas: Research Funding; Celgene, Genentech, Abbvie, Infinity, Cardinal Health: Consultancy. Karmali:Celgene: Speakers Bureau. Fishkin:Biogen: Other: Owns Stocks. Smith:Genentech: Consultancy, Other: on a DSMB for two trials ; Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Amgen: Other: Educational lecture to sales force; Portola: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy.

The feasibility of administering varying high-dose consolidation hyperthermic intraperitoneal chemotherapy with carboplatin in the treatment of ovarian carcinoma

Hyperthermic intraperitoneal chemotherapy (HIPEC) is an intriguing method of delivery wherein the cytotoxic agent is continuously heated and circulated throughout the peritoneum in an attempt to bolster drug efficacy. Despite HIPEC's potential, ascertaining the optimal dose without compromising patient tolerability remains indeterminate. We retrospectively evaluated 52 advanced stage ovarian cancer patients who were treated with consolidation HIPEC with carboplatin at varying doses (e.g., AUC 6, 8 or 10) subsequent to optimal debulking surgery and the attainment of a clinical complete response to their primary chemotherapy regimen. The following patient and operative characteristics were abstracted: demographics, surgery and pathology data, chemotherapy regimen, intraoperative results, toxicity, postoperative complications, length of hospital stay and survival data. Twelve patients received HIPEC carboplatin at an AUC 6, 15 subjects were treated with carboplatin at an AUC 8 and 25 underwent carboplatin at an AUC 10. There were no intraoperative complications during the administration of HIPEC; mean estimated blood loss was 50 mL and length of hospital stay was 1.65 days. In the overall study population, 5 patients developed grade 3/4 anemia and 33 subjects exhibited grade ≤2 thrombocytopenia and neutropenia. Thirteen patients also developed grade ≤2 nausea on postoperative day 1, which was successfully addressed with anti-emetic therapy; there were no hospital readmissions. The results from the current evaluation suggest that consolidation hyperthermic intraperitoneal chemotherapy with carboplatin is both feasible and reasonably tolerated, even at an AUC of 10. However, additional, randomized study of this procedure incorporating chemotherapy dose escalation with a more extensive patient population is warranted.

Front-Line, Dose-Escalated Immunochemotherapy Is Associated with a Significant PFS (but not OS) Advantage in 401 Patients (Pts) with Double-Hit Lymphomas (DHL): A Systematic Review and Meta-Analysis

Introduction: “Double-hit lymphoma” (DHL), characterized by the presence of both c-Myc and BCL-2 rearrangements, is an aggressive B-cell non-Hodgkin’s lymphoma (NHL) that is clearly associated with an inferior prognosis compared to standard risk DLBCL. DHL pts do poorly when treated with R-CHOP and typically cannot be salvaged once relapsed. Studies examining the treatment of DHL pts have been small and there is a lack of consensus in the lymphoma community as to whether DHL pts benefit from dose-escalated chemotherapy regimens in the front-line setting. To address this question, we generated pooled, meta-analytic estimates of the effectiveness of dose-escalated approaches vs. standard dose immunochemotherapy in prolonging overall survival (OS) and progression-free survival (PFS) in newly diagnosed DHL pts.Methods: DHL was defined by the presence of c-Myc rearrangement (FISH) in combination with BCL2 rearrangement (FISH) in pts with DLBCL or transformed follicular lymphoma. Treatment regimens included dose intensive (DI; R-Hyper-CVAD, R-CODOX-M/IVAC), intermediate dose [Dose adjusted (DA)-R-EPOCH], or standard dose (R-CHOP). PubMed, Embase, and abstracts at 3 specific congresses from 1/2009 to 6/2014 were searched using terms “lymphoma” with “DHL”, “dual hit”, “dual translocation”, “double-hit”, or “myc” and “bcl2”. Randomized controlled trials and observational studies evaluating treatment of DHL were eligible for inclusion. Studies of ≤ 10 DHL pts were excluded. Data were collected from study authors or extracted from publications as the proportions of pts surviving at specific follow-up times or individual event times. Data were synthesized to estimate the hazard ratios of higher-dose treatments relative to R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework.Results: The initial search yielded 996 hits and 57 congress abstracts. After independent review by three investigators, 11 studies examining 401 pts were included in the analysis. Pts were treated with either R-CHOP (n=180), DA-R-EPOCH (n=91), or DI regimen (n=130) in the front-line setting. There were no significant differences in baseline characteristics of pts between included studies or across treatment regimens (median age at diagnosis 60 years, median Ki-67 88%, 53% IPI ≥ 3). The estimated median (and 95% credible intervals [CrIs; the Bayesian analog to confidence intervals]) OS and PFS for the entire cohort were 27.8 (15.1-48.5) and 20.5 (10.9-36.0) months. No significant differences in OS (n=374) were observed among any of the treatments (estimated med OS: R-CHOP, DA-R-EPOCH and DI were 24.2, 37.5, and 29.5 months, respectively, Figure A). Estimated hazard ratios (HR) of OS were 0.77 (95% CrI: 0.50-1.11) for DA-R-EPOCH and 0.90 (95% CrI: 0.62-1.25) for DI relative to R-CHOP. The PFS (n=357) among pts receiving DA-R-EPOCH (HR 0.64, 95% CrI: 0.42-0.92) or DI (HR 0.75, 95% CrI: 0.51-1.05) was similar and DA-R-EPOCH demonstrated significant improvement over R-CHOP (estimated med PFS: R-CHOP, DA-R-EPOCH and DI of 13.9, 27.8, and 21.9, respectively, Figure B).Conclusions: In the largest study and first meta-analysis of treatment outcomes in DHL pts, we have demonstrated that dose-escalated chemotherapy was associated with a significant increase in PFS (particularly DA-R-EPOCH) which did not translate into an OS advantage. This suggests DHL is a disease of chemotherapy resistance. One can consider the use of dose-escalated front-line therapies as they can lead to a PFS advantage and that consolidation strategies should be developed to reduce the likelihood of relapse. These results highlight (1) outcomes remain poor for DHL pts regardless of the intensity of R-chemotherapy induction (2) the need for routine screening for MYC and BCL2 by FISH in DLBCL pts with high-risk features and (3) the need for prospective induction and consolidation strategies that incorporate our growing understanding of the biological basis of DHL such as combinations of novel targeted therapies and/or upfront consolidation with CAR-T-cells. [Display omitted] DisclosuresCohen:Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Mato:Celgene: Honoraria, Research Funding.

Evolution of treatment for nasopharyngeal cancer – Success and setback in the intensity-modulated radiotherapy era

Background and purposeTo assess the therapeutic gains and setbacks as we evolved from the 2-dimensional radiotherapy (2DRT) to conformal 3-dimensional (3DRT) and to intensity-modulated (IMRT) era. Materials and methods1593 consecutive patients from 1994 to 2010 were retrospectively analyzed. Evolving changes in the different era included advances in staging investigation, radiotherapy technique, dose escalation, and use of chemotherapy. ResultsThe 3DRT era achieved significant improvement in local failure-free rate (L-FFR), disease-specific survival (DSS) and overall survival (OS). Neurological damage and bone/soft tissue necrosis were significantly reduced. However, the improvement in distant failure-free rate (D-FFR) was insignificant, and more hearing impairment occurred due to chemotherapy. Significantly higher D-FFR was achieved in the IMRT era, but L-FFR did not show further improvement. 5-Year DSS increased from 78% in the 2DRT, to 81% in the 3DRT, and 85% in the IMRT era, while the corresponding neurological toxicity rate decreased from 7.4% to 3.5% and 1.8%. ConclusionsSignificant improvement in survival and reduction of serious toxicity was achieved as we evolved from 2DRT to 3DRT and IMRT era; the therapeutic ratio for all T-categories improved with more conformal techniques. Improvements in tumor control were attributed not only to advances in RT technique, but also to better imaging and increasing use of potent chemotherapy. However, it should also be noted that hearing impairment significantly increased due to chemotherapy, L-FFR reached a plateau in the 3DRT era, and it is worrisome that the result for T4 remained unsatisfactory. Besides exploring for more potent chemotherapy and innovative methods, the guideline on dose constraint should be re-visited to optimize the therapeutic ratio.

Current state of art for transplantation paradigms in peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) are a rare and aggressive lymphoproliferative disorder characterized, with few exception, by poor prognosis. A correct diagnosis is still hampered by the heterogeneity and rarity of disease. Historically, PTCLs were treated like aggressive B-cell lymphoma with anthracycline-based combination chemotherapy with disappointing results. Neither dose intensification nor dose escalation of chemotherapy has been successful in prolonging the survival of PTCL patients. Due to this discouraging scenario, new therapeutic strategies have been tested. A therapeutic program including hematopoietic stem-cell transplantation (SCT) may represent an interesting strategy for high-risk patients. Although no randomized trials are available, autologous SCT may offer a chance of cure in chemosensitive disease. Nonmyeloablative allogeneic SCT has shown a curative potential with limited toxicity, and it is actively being investigated. We will review the role of the current therapeutic approach to PTCL focusing on the most recent advances in SCT.

Phase I Dose Escalation of Doxorubicin Chemotherapy in Tumor‐Bearing Equidae

There is no information on the use of doxorubicin in horses with tumors. To determine dose-limiting toxicosis (DLT) and maximum tolerated dose (MTD) of doxorubicin in tumor-bearing horses. Seventeen horses with 34 localized or multicentric advanced tumors. Two-stage dose-ranging design involving intrapatient and interpatient dose escalation. Treatment protocol included 6 treatment cycles given at 3-week intervals with dosages ranging from 40 to 85 mg/m(2). Clinical signs, hematologic, and nonhematologic changes were evaluated. Total doses ranged from 1,127 to 2,900 mg in 12 horses that completed the assigned treatment protocols. The MTD was 75 mg/m(2). Hypersensitivity reactions and neutropenia were dose limiting. Hypersensitivity was dose-dependent but schedule invariant. Neutropenia was dose- and cycle-dependent but dose-escalation schedule invariant. Cardiotoxicity was not observed. The recommended dosage of doxorubicin to treat horses is 70 mg/m(2) given at 3-week intervals as single agent. Adjunctive treatment with antihistamines and nonsteroidal anti-inflammatory drugs is recommended to control hypersensitivity.

Different administration strategies with paclitaxel induce distinct phenotypes of multidrug resistance in breast cancer cells

Both dose-dense and dose-escalation chemotherapy are administered in clinic. By approximately imitating the schedules of dose-dense and dose-escalation administration with paclitaxel, two novel multidrug resistant (MDR) cell lines Bads-200 and Bats-72 were successfully developed from drug-sensitive breast cancer cell line BCap37, respectively. Different from Bads-200, Bats-72 exhibited stable MDR and significantly enhanced migratory and invasive properties, indicating that they represented two different MDR phenotypes. Our results showed that distinct phenotypes of MDR could be induced by altered administration strategies with a same drug. Administrating paclitaxel in conventional dose-escalation schedule might induce recrudescent tumor cells with stable MDR and increased metastatic capacity.