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1
Tankel, James, and Lorenzo Ferri. "New Approaches to Neoadjuvant Treatment for Locally Advanced Esophageal Cancer." Foregut: The Journal of the American Foregut Society 2, no. 2 (June 2022): 143–53. http://dx.doi.org/10.1177/26345161221108331.
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The treatment paradigm of esophageal carcinoma is evolving as is the appreciation that histology drives treatment decisions. For adenocarcinoma, neoadjuvant chemotherapy followed by en bloc transthoracic resection is the gold standard of care. In this setting, the addition of radiotherapy does not seem to be associated with a survival benefit. For squamous cell carcinoma, neoadjuvant chemoradiotherapy is currently the best therapeutic option. However, modern neoadjuvant chemotherapy regimens may engender better survival outcomes for these patients too. Moreover, the role of immunomodulating therapies and selective surgical approaches are yet to be fully appreciated and may influence future recommendations.
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Passardi, Alessandro, Emanuela Scarpi, Luigi Cavanna, Annalisa Fontana, Bernadette Vertogen, Silvia Ruscelli, Emiliano Tamburini, et al. "Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3517. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3517.
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3517 Background: Evidence from available RCTs indicates that the addition of bevacizumab (B) to chemotherapy (CT) results into an improved survival in metastatic colorectal cancer (mCRC). However, the magnitude of this effect is different across trials, with marginal benefit observed when gold standard CT regimens are used. With these premises we performed a phase III randomized clinical study to evaluate the effectiveness of gold standard mCRC first line CT + B. This study was funded by the Italian Ministry of Health. Methods: mCRC patients candidate were randomized to receive first line CT +B or first line CT alone. CT regimens included FOLFOX4 (oxaliplatin 85 mg/m2 d1, folinic acid FA 100 mg/m2 dd1,2, 5FU 400 mg/m2 iv bolus dd 1,2 plus 5FU 600 mg/m2 22-h ic dd1,2 – Q14 days) or FOLFIRI (irinotecan 180 mg/m2d1, FA and 5FU as in FOLFOX4, Q 14 days); B 5 mg/kg was administered Q 14 days. The primary end point was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (ORR) and safety. Three hundreds ten events were required to statistically differentiate PFS between groups with 80% power. Results: Between 11/2007 and 03/2012, 376 patients were randomized. Patient characteristics were well balanced between the two arms. FOLFOX4 was used in 60% of the patients and FOLFIRI in 40%. After a median follow up of 18.4 months, 313 progressions and 179 deaths were observed. No statistically significant differences in PFS, OS and ORR were observed (see table). B containg regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. Conclusions: The addition of B to a gold standard CT for mCRCdoes not result into an improved prognosis in terms ofPFS, ORR, OS. ITACA’s results (control arm) suggest that the chemotherapeutic schedules used in some of the previously published bevacizumab trials might be suboptimal. Clinical trial information: 2007-004539-44. [Table: see text]
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Eldridge, Sandy, Liang Guo, and John Hamre. "A Comparative Review of Chemotherapy-Induced Peripheral Neuropathy in In Vivo and In Vitro Models." Toxicologic Pathology 48, no. 1 (July 22, 2019): 190–201. http://dx.doi.org/10.1177/0192623319861937.
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Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect caused by several classes of widely used anticancer therapeutics. Chemotherapy-induced peripheral neuropathy frequently leads to dose reduction or discontinuation of chemotherapy regimens, and CIPN symptoms can persist long after completion of chemotherapy and severely diminish the quality of life of patients. Differences in the clinical presentation of CIPN by widely diverse classifications of anticancer agents have spawned multiple mechanistic hypotheses that seek to explain the pathogenesis of CIPN. Despite its clinical relevance, common occurrence, and extensive investigation, the pathophysiology of CIPN remains unclear. Furthermore, there is no unequivocal gold standard for the prevention and treatment of CIPN. Herein, we review in vivo and in vitro models of CIPN with a focus on histopathological changes and morphological features aimed at understanding the pathophysiology of CIPN and identify gaps requiring deeper exploration. An elucidation of the underlying mechanisms of CIPN is imperative to identify potential targets and approaches for prevention and treatment.
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Arjunan, Ananth, and Hema Rai. "Central Nervous System Involvement by Waldenstrom Macroglobulinemia: A Case Report of the Bing–Neel Syndrome." Case Reports in Hematology 2019 (March 14, 2019): 1–3. http://dx.doi.org/10.1155/2019/4075960.
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Bing–Neel syndrome (BNS) is a rare complication of Waldenstrom macroglobulinemia (WM) defined by a lymphoplasmacytic infiltration of the central nervous system (CNS). Patients present with a range of neurologic symptoms of variable severity. Diagnosis requires a low threshold of suspicion and is considered in WM patients with unexplained neurologic symptoms. It can occur in the presence of quiescent serum markers of WM. Direct CNS tissue biopsy should be pursued if feasible and remains the gold standard for diagnosis. No standard of care treatment exists, but expert guidelines suggest intravenous chemotherapy in standard dose or high-dose regimens or use of oral ibrutinib. Consideration is also made for intravenous rituximab, intrathecal therapies, and autologous stem cell transplantation. Patient factors and tolerability should drive decisions regarding treatment choice in this arena, given a lack of data for standard frontline therapy.
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Jung, Sara, Zoltan Nagy, Martin Fassnacht, Gerard Zambetti, Max Weiss, Martin Reincke, Peter Igaz, Felix Beuschlein, and Constanze Hantel. "Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma." Endocrine-Related Cancer 23, no. 10 (October 2016): 825–37. http://dx.doi.org/10.1530/erc-16-0249.
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Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo. We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.
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Bila, Jelena, Mirjana Gotic, and Biljana Mihaljevic. "New concept of the treatment in elderly patients with multiple myeloma." Srpski arhiv za celokupno lekarstvo 139, suppl. 2 (2011): 110–15. http://dx.doi.org/10.2298/sarh11s2110b.
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The traditional concept of treatment of patients aged over 65 years with multiple myeloma is historical combination of melphalan and prednisone (MP). The introduction of novel agents, such as immunomodulatory drugs and proteasome inhibitors, has crucially changed the course and prognosis of this disease. The new gold standard of treatment in elderly patients with multiple myeloma is based on synergistic combination of standard MP chemotherapy and novel agents such as thalidomide and bortezomib, as a part of MPT and MVP regimens. Furthermore, promising results have been also obtained with MP plus new generation of immunomodulatory drug lenalidomide. In some patients aged over 65 years and in good general condition, reduced-intensity autologous stem cell transplantation can be an option with application of reduced intensity conditioning regimens and novel agents incorporated into pre-transplant induction treatment and post-transplant consolidation. Certain concern regarding treatment-related adverse events can be overcome by adequate prophylaxis, conscientious follow-up, timely dose-reduction, and application of reducedintensity MPT and MPV in patients aged over 75 years. The last therapy of choice should be individually tailored according to the clinical profile of the patient and expected toxic effects of planned treatment.
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Irino, Tomoyuki, Hiroya Takeuchi, Masanori Terashima, Toshifumi Wakai, and Yuko Kitagawa. "Gastric Cancer in Asia: Unique Features and Management." American Society of Clinical Oncology Educational Book, no. 37 (May 2017): 279–91. http://dx.doi.org/10.1200/edbk_175228.
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Gastric cancer (GC) poses a burden to patients across the globe as the third leading cause of cancer deaths worldwide. Incidence of GC is particularly high in Asian countries, which is attributed to the prevalence of Helicobacter pylori (H. pylori) infection and has prompted the establishment of unique treatment strategies. D2 gastrectomy, which was established in the 1950s in Japan, has served as a gold standard for locally advanced GC for over half a century. Since the beginning of the 21st century, endoscopic resection (ER) techniques and minimally invasive laparoscopic surgery have greatly changed the treatment of patients with early GC. S-1, which showed a striking survival benefit in a large randomized trial in Japan, has been used as adjuvant therapy for the last decade. Likewise, S-1–based chemotherapy regimens are currently the standard of care for the treatment of unresectable/metastatic GC in Asia. Along with the development of standardized therapy, novel techniques and new drugs have been rapidly brought into clinical practice. State-of-the-art sentinel node (SN) navigation surgery enables clinicians to perform truly minimally invasive surgery for early GC, and appropriate chemotherapy regimens are now determined by a tumor’s molecular expression. New classifications based on gene signatures are proposed and may replace conventional clinical classifications. Such highly individualized treatment has the potential to alter our clinical practice in GC in the near future. The best practice in each geographic region should be shared and integrated, resulting in the best practice without borders.
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Affronti, M. L., J. M. Day, J. E. Herndon, J. N. Rich, J. A. Quinn, D. A. Reardon, J. J. Vredenburgh, A. Desjardins, R. E. McLendon, and H. S. Friedman. "Radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy for glioblastoma (GBM) patients." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2068. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2068.
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2068 Background: GBM is the most lethal type of brain tumor with a 1 yr median survival. We hypothesized that GBM patients who receive adjuvant rotational multi-agent chemotherapy (temozolomide, CCNU, and CPT-11) have improved overall survival when compared to patients receiving single agent adjuvant regimens (carmustine, temozolomide). Methods: We conducted an IRB-approved retrospective data analysis of 80 primary GBM patients who received radiation therapy and concurrent temozolomide followed by 12 mos of adjuvant rotational multi-agent chemotherapy. All patients with the intent to treat were included in the analysis. The survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA). These data were compared to the recently published Stupp RPA analysis (JCO 2006) and the RTOG trial (radiation alone). Results: 73% were male. Mean age was 52 yrs (range 21–76 yrs); 39 % were < 50 yrs.. 82% were white. WHO performance status was: 0, 14%; 1, 62%; 2, 20%; and 3, 4%. Overall survival was 59% (95% CI: 49%, 71%) at 1 yr and 31% (23%, 43%) at 2 yrs. Median survival was 65.1 wks (49.7, 78.9) with median follow-up of 122.1 wks.. No difference in the 2-yr overall survival rate in RPA classes III-IV was detected between the Duke and Stupp regimens (p>0.4733), but 66% (33, 77) of the Duke rotational therapy GBM patients are living longer than the RTOG patients (p > 0.0086). Univariate Cox Hazard ratio of 1.27 (0.522, 3.08) did not correlate MGMT status with survival (p > 0.60). Conclusions: (1) Concurrent Temozolomide and radiation followed by rotational chemotherapy is an effective therapy compared to recent published gold standard adjuvant regimens. (2) Concurrent Temozolomide and radiation followed by rotational chemotherapy resulted in a statistically significant survival benefit compared to RTOG trial. (3) Lack of correlation between MGMT and overall survival suggests that agents whose damage is not repaired by MGMT may be an important therapeutic approach. (4) Future prospective randomized trials with concurrent Temozolomide and radiation must compare post radiation multi-modality regimens. No significant financial relationships to disclose.
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Morris, Julia M., and Curtis A. Thorne. "Abstract 3087: The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3087. http://dx.doi.org/10.1158/1538-7445.am2022-3087.
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Abstract Resistance to chemotherapy drugs is a well-documented issue inhibiting the treatment of a wide variety of cancers. Colorectal cancer (CRC) is the third most common neoplasm worldwide and has the third highest mortality rate. However, the longtime gold-standard FOLFOX chemotherapy regimen, consisting of 5-FU and Oxaliplatin, results in only 70% survival rates in Stage 3 CRC patients, worse in Stage 4. More recent targeted therapies have marginally improved on this number, but the fact remains that CRC represents a highly heterogeneous neoplasm and resistance to standard chemotherapeutic regimens poses a significant barrier in treating this devastating disease. There is an immediate need to better understand how this resistance arises. We hypothesize that a small number of cells with high phenotypic plasticity (HPP) are able to remain dormant during the initial chemotherapy treatment then reenter the cell cycle to cause recurrence and metastasis months or even years after treatment has concluded. Patient-derived organoids (PDOs) are a recently developed ex vivo model that allows for the study and extensive characterization of such HPP cell populations that may be found in patient tumors. We are developing and expanding various PDO populations to examine them genotypically and phenotypically on the single-cell level through RNA sequencing and high throughput imaging, respectively. By identifying these HPP cell populations, we then discover drugs that prevent the development of drug-resistant subpopulations. In the long term, we use our tumor heterogeneity profile to develop models that predict the responsiveness of tumors, including their drug-resistant HPP subpopulations, to well-documented and clinically used oncology drugs, streamlining treatment and improving survival outcomes. Citation Format: Julia M. Morris, Curtis A. Thorne. The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids [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 3087.
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Bredin, Philip, Joseph J. McKendrick, Prasad Cooray, and Rachel Wong. "Small bowel adenocarcinoma treatment: A single centre experience." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 451. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.451.
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451 Background: Small bowel adenocarcinoma (SBA) has a high mortality. Randomised controlled trials are not feasible due to its rarity, therefore there is no gold standard treatment approach. Surgical resection for early stage disease is the only potentially curative option. Systemic therapeutic options are generally extrapolated from oesophagogastric and colorectal chemotherapy regimens. Methods: This is a retrospective review of treatment and outcomes for SBA patients who attended Eastern Health between 1st January 2010 and 30thJune 2015. Approval was obtained from the Eastern Health Human Research and Ethics Committee. Results: Thirty-six patients with SBA were identified: 16 (44%) duodenal, 12 (33%) ampullary, 6 (17%) jejunal, 2 (6%) terminal ileum, 1 not specified. Median age was 72 and 25 (69%) were male. Stage at diagnosis was as follows: Stage 1 = 4 (11%), Stage 2 = 8 (22%), Stage 3 = 9 (25%) and Stage 4 = 10 (28%). Surgery with curative intent occurred in 19 patients (Whipple’s = 13, wide local excision = 6) of whom 6 received adjuvant (predominantly fluoropyrimidine-based) chemotherapy. One patient died from post-operative complications. At last follow-up, 8 patients remained in complete remission; 11 had relapsed; 3 were lost to follow-up. Three patients had died due to disease. Median relapse-free survival in the curative-intent group was 21.4 months. Median overall survival (OS) has not been reached. Sixteen patients were initially treated with palliative intent. Ten underwent palliative surgery (bypass = 7; resection = 3). Overall, 16 patients commenced palliative chemotherapy, including 8 from the curative-intent group post-relapse. The most commonly used regimen was oxaliplatin plus fluoropyrimidine. Best responses to chemotherapy were partial response = 5 (31%) and stable disease = 4 (25%). Six patients received second-line chemotherapy. Median progression-free survival on first-line chemotherapy was 4.8 months. Median OS was 9.4 months. Conclusions: SBA has a poor prognosis. Although 56% of advanced SBA patients had disease control using chemotherapy extrapolated from other gastrointestinal malignancies, responses were not durable.
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Minarik, Jiri, Edgar Faber, Ludek Raida, Tomas Szotkowski, Jaroslav Bacovsky, Tomas Pika, Ivana Skoumalova, et al. "20 Years of Transplant Program in Multiple Myeloma - a Single Centre Experience." Blood 132, Supplement 1 (November 29, 2018): 5749. http://dx.doi.org/10.1182/blood-2018-99-112115.
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Abstract Aims: The aim is to present the results of 20 years of autologous stem cell transplant (ASCT) program in multiple myeloma (MM) at our site. Patients and methods: Since 1997 till 2017, a cohort of 348 patients underwent ASCT at the Department of Hemato-Oncology of the University Hospital Olomouc. Altogether 274 were 1st ASCT, 62 were 2nd transplants, the rest were tandem or third ASCT. The patients had standard baseline characteristics, including age, gender, immunoglobulin and light chain type, Durie-Salmon (DS) and International Staging System (ISS). The induction regimens for 1st ASCT included VAD (vincristin, adriamycine, dexamethasone) in 34%, THAL in 15%, BTZ based regimens in 34%, the rest (17%) were combined polychemotherapeutic regimens. The re-induction regimens before 2nd ASCT included CAD (cyclophosphamide, adriamycine, dexamethasone) in 27%, BTZ in 31% and THAL based regimens in 18%, other patients (24%) had LEN based regimens, polychemotherapy or no re-induction. 163 patients (47%) had maintenance, mostly interferon based (25%), conventional chemotherapy based (9%) or THAL based (7%), and 53% of patients had no maintenance. We assessed response rates, ie the rate of complete remission (CR), very good partial remission (VGPR), partial remission (PR), minimal response (MR), stable disease (SD), progressive disease (PG) and overall response rate (ORR) based on International Myeloma Working Group (IMWG) criteria. The survival measures of individual treatment lines were assessed by means of progression free survival (PFS). We assessed the efficacy of ASCT with respect to treatment line, pre-transplant and post transplant response achieved (day+100), and with respect to DS and ISS as well as to treatment modality used for induction and maintenance. For statistical estimation we used Kaplan-Meier curves, Log rank test (Mantel-Cox), Post-hoc tests according to Dunn, Pearson ChiSquare test, Fisher´s Exact Test, Kruskal-Wallis test, and McNemar-Bowker Test. Results: The response rates after 1st ASCT were following: CR 32,1%, VGPR 26,5%. PR 34,8%, MR and SD 3% and PG 3,4%. Median PFS after 1st ASCT was 35 months and it corresponded to the depth of treatment response: CR 48 months, VGPR 36 months, PR 33 months, MR and SD 13 months, PG 9 months, p<0,0001. Pre-transplant responses showed a trend towards better outcomes with deeper responses but beyond statistical significance (p = 0,077). Advanced DS stage correlated with worse PFS (stage I 58 months, stage II 42 months, stage III 31 months). Patients under age 59 years tended to have slightly better PFS (37 vs 34 months, p = 0,078). Both pre and posttransplant responses were significantly better after novel drugs than conventional chemotherapy, still, there was no statistically significant difference in PFS. None of the maintenance (chemotherapy, interferon, THAL-based) lead to a better PFS. There were very few patients treated with BTZ, LEN or ixazomib maintenance precluding valid statistical analysis. There were no differences in either responses or PFS with regard to treatment line but there were only 19 patients not having ASCT as their first regimen. The response rates after 2nd ASCT were as follows: CR 26,7%, VGPR 13,3%, PR 38,3%, MR+SD 8,3% and PG 13,3%. Median PFS after 2nd ASCT was 20 months, decreasing with inferior responses (CR 34,8 months, VGPR 22,5 months, PR 33,1 months, MR and SD 18,8 months, PG 6,6 months p<0,0001). There were no differences in PFS with respect to either ISS, DS stage or re-induction regimen. Patients transplanted in their first relapse tended to have better PFS than in later relapses. Conclusion: The use of ASCT is still the gold standard in MM. Regardless of treatment line, it achieves significant outcomes. Novel drugs induce deeper pre-transplant responses, still, the major advantage against conventional chemotherapy is in the speed of response and absence of severe adverse events, enabling more patients to reach ASCT. Maintenance therapy accounts for better survival, however, this is true only for novel drugs (such as bortezomib, lenalidomide) whereas older modalities including interferone, post-transplant chemotherapy, steroids or thalidomide do not possess such activity. The second ASCT is comparable to to current treatment modalities in relapsed MM with fair post-transplant outcomes as well as PFS, with high rate of complete responses. Supported by the grant IGA-LF-2018-004 andMH CR - RVO (FNOl, 00098892). Disclosures No relevant conflicts of interest to declare.
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Kigawa, J., M. Shimada, Y. Minagawa, Y. Kanamori, H. Itamochi, F. Kitada, M. Okada, and N. Terakawa. "Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 15055. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.15055.
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15055 Background: The carboplatin-paclitaxel combination therapy is a gold standard regimen for patients with ovarian cancer. However, combination chemotherapy continues to produce significant neurotoxicity, a serious adverse effect. We conducted the present study to determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. Methods: Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m2 and cisplatin 60 mg/m2 or carboplatin to an area under the curve = of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. Results: Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) vs. 74% (20/27)]. Conclusions: Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer. No significant financial relationships to disclose.
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Morell, Anselm, Lucie Čermáková, Eva Novotná, Lenka Laštovičková, Melodie Haddad, Andrew Haddad, Ramon Portillo, and Vladimír Wsól. "Bruton’s Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3." Cancers 12, no. 12 (December 11, 2020): 3731. http://dx.doi.org/10.3390/cancers12123731.
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Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.
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Zlotta, Alexandre R., Neil E. Fleshner, and Michael A. Jewett. "The management of BCG failure in non-muscle-invasive bladder cancer: an update." Canadian Urological Association Journal 3, no. 6-S4 (May 1, 2013): 199. http://dx.doi.org/10.5489/cuaj.1196.
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Up to 40% of patients with non-muscle-invasive bladder cancer(NMIBC) will fail intravesical bacillus Calmette-Guérin (BCG)therapy. There is unfortunately no current gold standard for salvageintravesical therapy after appropriate BCG treatment. Indeed,outcomes are at best suboptimal. The vast majority of low-gradeNMIBC are prone to recur but very rarely progress. Failure afterintravesical BCG in these patients is usually superficial and lowgrade.At the other end of the spectrum, failure to respond to BCGin high-risk T1 bladder cancer and/or carcinoma in situ (CIS orTIS) is more problematic, since those tumours often have the potentialto progress to muscle invasion. In these cases, radical cystectomyremains the mainstay after BCG failure. With appropriateselection, certain patients who “fail” BCG (but with favourablerisk factors) can be managed with intravesical regimens, includingrepeated BCG, BCG plus cytokines, intravesical chemotherapy,thermochemotherapy or new immunotherapeutic modalities. Inthis review, reasons explaining BCG failure, how to define BCGfailure, optimal risk stratification and prediction of response andmanagement of BCG failures are discussed.
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Jones, Kellie L., and Aman U. Buzdar. "A review of adjuvant hormonal therapy in breast cancer." Endocrine-Related Cancer 11, no. 3 (September 2004): 391–406. http://dx.doi.org/10.1677/erc.1.00594.
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Breast cancer is the most common carcinoma diagnosed in women today excluding non-melanoma skin cancers. It has been well documented that estrogen plays a critical role in its development and is a major target for treatment. For many years, tamoxifen has been the gold standard for adjuvant hormonal therapy in breast cancer patients. With newer products targeting different mechanisms to suppress estrogen production, patients now have many decisions regarding their care. Agents such as luteinizing hormone releasing hormone (LHRH) agonists can suppress ovarian function in premenopausal patients and have been shown to be as effective and even better than chemotherapy (CMF — cyclophosphamide, methotrexate, fluorouracil-containing regimens) in certain patient populations. Tamoxifen continues to be an option as well as toremifene, a similar selective estrogen receptor modulator. With the advent of newer third generation aromatase inhibitors (anastrozole, letrozole and exemestane) toxicities have been documented to be less and in some cases they are more efficacious than the standard, tamoxifen. This article reviews the current data regarding ovarian suppression, ovarian suppression plus tamoxifen, tamoxifen, toremifene, anastrozole, letrozole, and exemestane in the treatment of adjuvant hormonal-sensitive breast cancer.
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Papayannidis, Cristina, Anna Candoni, Stefania Paolini, Emanuela Ottaviani, Ilaria Iacobucci, Michela Rondoni, Michele Malagola, et al. "Induction Intensified Regimens Including Fludarabine or Mylotarg for Acute Myeloid Leukemia Patients: Comparison by Response and Follow-up." Blood 112, no. 11 (November 16, 2008): 941. http://dx.doi.org/10.1182/blood.v112.11.941.941.
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Abstract Background . Conventional induction treatment in young Acute Myeloid Leukemia (AML) patients (<= 60 years old) is still represented by the association of antracycline and cytarabine, which offers a complete remission (CR) rate not inferior to 63%. Since many non-randomized trials have recently demonstrated the superiority of intensified regimens, the present gold standard therapy includes the addition of at least a third drug to the classic 3/7 schedule. Aim of the study . We evaluated the safety profile and the efficacy of two four-drugs induction schedules, adding either fludarabine (25 mg/sqm days 1–5) or mylotarg (3 mg/sqm day 6) to idarubicin (6 mg/sqm days 1, 3, 5), cytarabine (1 g/sqm days 1–5), etoposide (100 mg/sqm days 1–5) (FLAIE and MyAIE, respectively). Methods . Sixty-six consecutive AML patients were enrolled either in the FLAIE (N=44, from 2002 to 2005) or in the MyAIE (N=22, from 2005 to April 2007) schedule, with similar clinical and biological characteristics. The median age was 45 and 48 years, respectively. According to kariotype, WBC count and FLT3 status, seventy and sixty-four percent of cases, respectively, were considered at high risk. Consolidation therapy consisted of 2 cycles of ID-AraC and Ida. Results . The complete remission rate was 75% and 59% for FLAIE and MyAIE, respectively (p=n.s.). Death during treatment rates were 5% and 0. After 1 consolidation course the overall CR rate was 80% and 73%. After a similar median follow up, 27 months (1–62) and 21 months (5–42) respectively, 41% of patients are alive in CR in the FLAIE group (12 SCT and 3 ASCT) and 64% in the MyAIE group (7 SCT and 4 ASCT) (p=n.s.; Chi-square, Fisher’s exact test). Toxicity was comparable in the two regimens. The median time to ANC recovery (>1.0 x 10^9/L) was 31 and 23 days for FLAIE and MyAIE, respectively. The median time to PLT recovery (>100 x 10^9/L) was 28 and 24 days, respectively. The median time of neutropenic fever episodes for patients was 1 and 1.4 in the 2 groups, respectively. Grade III/IV GI toxicities occurred in 11% and 22% of cases, respectively. Conclusions . These data showed that four-drugs intensified induction therapy is a feasible approach in young AML patients. Recent published trials have demonstrated that fludarabine-based induction chemotherapy in high risk AML patients is able to increase the CR rate offered by conventional treatment. Therefore, the limited number of patients involved in this study, the low administration dosage of idarubicin, and the relevant role of fludarabine in induction therapy, can reasonably justify the lower CR rate obtained in patients treated in the MyAIE schedule, if compared with FLAIE regimen and, above all, with standard chemotherapy. In the light of their efficacy and safety profile, fludarabine and mylotarg, in combination with conventional chemotherapy, represent a promising induction regimen in young AML patients; further analyses and randomized pilot trials will define their definite role.
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Bladé, Joan, Laura Rosiñol, Maria Teresa Cibeira, Montserrat Rovira, and Enric Carreras. "Hematopoietic stem cell transplantation for multiple myeloma beyond 2010." Blood 115, no. 18 (May 6, 2010): 3655–63. http://dx.doi.org/10.1182/blood-2009-08-238196.
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AbstractAutologous stem cell transplantation (ASCT) is considered the gold standard in the frontline therapy of younger patients with multiple myeloma because it results in higher complete remission (CR) rates and longer event-free survival than conventional chemotherapy. The greatest benefit from ASCT is obtained in patients achieving CR after transplantation, the likelihood of CR being associated with the M-protein size at the time of transplantation. The incorporation of novel agents results in higher pre- and posttransplantation CR rates. Induction with bortezomib-containing regimens is encouraging in patients with poor-risk cytogenetics. However, longer follow-up is required to assess the impact of this increased CR on long-term survival. The results of posttransplantation consolidation/maintenance with new drugs are encouraging. All this indicates that, in the era of novel agents, high-dose therapy should be optimized rather than replaced. Because of its high transplantation-related mortality, myeloablative allografting has been generally replaced by reduced-intensity conditioning (reduced intensity conditioning allogeneic transplantation). The best results are achieved after a debulky ASCT, with a progression-free survival plateau of 25% to 30% beyond 6 years from reduced intensity conditioning allogeneic transplantation. The development of novel reduced-intensity preparative regimens and peri- and posttransplantation strategies aimed at minimizing graft-versus-host disease, and enhancing the graft-versus-myeloma effect are key issues.
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Malavasi, N., C. Dealis, R. Depenni, S. Zironi, F. Bertolini, L. Losi, G. E. Gerunda, G. Colucci, G. Luppi, and P. F. Conte. "Phase II trial to evaluate combination of folfox6 + bevacizumab in initially unresectable liver metastases from colorectal cancer (crc)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14603. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14603.
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14603 Introduction: The gold standard treatment of CRC liver metastases is surgical resection. Bevacizumab has proved efficacy in advanced disease. Primary objective of the study is to evaluate resecability rate of liver metastases and incidence of major surgery complications. Secondary objective is to relate tumor and serum biomarkers (EGFR, VEGF, TS, Ki67, ERCC1, MSH2, MLH1 and VEGF ) to clinical outcome Methods: Baseline requires evaluation by CT-PET scan, biopsy of metastases; PET scan is needed after first administration to describe preliminary response. The treatment consists of FOLFOX6 regimen associated to Bevacizumab, 5mg/Kg, every two weeks; elective surgery is planned after 6 cycles (the last one excludes Bevacizumab dose) by CT-PET scan; if resection is appropriate, it will be performed, otherwise the treatment will continue to 12 cycles. Biomarkers are assessed at baseline, following the first administration and before surgery Results: Up to now 11 patients have been enrolled (M/F:6/5; median age:64, range:46–72); ECOG: 0/1. 10 patients reached surgical step while 1 patient is still on chemotherapy. Three patients (27%) were not suitable for resection and received further chemotherapy: 1 had PR, 1 PD and 1 became resectable after 12 cycles. In the other 7 patients (63%): 2 CR (18%) histologically confirmed; 4 macroscopic and curative resection of liver metastasis; 1 is receving two stage epathectomy (portal vein occlusion before major liver resection). Life threatening toxicities: 1 TVP causing discontinuation of Bevacizumab, 1 hospitalization for gastro-intestinal and G4 neutropenia both causing discontinuation of the whole therapy. Bevacizumab complications before major surgery did not occurred; 1 patient reported post operative delay wound healing. Less severe toxicities: haematological G3 in 2 patients (18%), G1 in 1 patient (9%); 3 gastrointestinal G2 (27%); neuropathic in 1 patient (9%). The VEGF serum decreased after the first dose of Bevacizumab in all specimens Conclusions: Systemic chemotherapy with combination regimens may downstage liver metastases and thus increase resecability rate without important surgery complications; biomarkers related to clinical outcome are in evaluation. No significant financial relationships to disclose.
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Enns, Deborah L., and David Aboulafia. "Utility Of Routine Left Ventricular Ejection Fraction (LVEF) Measurement Prior To Administration Of Anthracycline-Based Chemotherapy In Patients With Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 122, no. 21 (November 15, 2013): 5599. http://dx.doi.org/10.1182/blood.v122.21.5599.5599.
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Abstract Anthracycline-based chemotherapy regimens are considered the gold standard for treating patients with DLBCL. Prior to administration of chemotherapy, LVEF is routinely measured, usually by multiple-gated acquisition (MUGA) scans or echocardiography, as a screening tool for detecting asymptomatic left ventricular dysfunction. LVEF screening is recommended by the National Comprehensive Cancer Network clinical practice guidelines, is endorsed by the American Heart Association and the American College of Cardiology, appears on Federal Drug Administration-approved labeling guidelines, and is often required for patients to participate in US cancer cooperative group clinical trails. However, despite these recommendations, evidence supporting the utility of LVEF measurement prior to administration of anthracycline-based chemotherapy in patients with DLBCL is lacking (Conrad, J Oncol Pract 2012). The most common chemotherapy regimen currently administered to DLBCL patients is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients with stage III or IV DLBCL typically receive 6 to 8 cycles of R-CHOP, with cumulative doses of doxorubicin ranging from 300 - 400 mg/m2. Cumulative doses of doxorubicin greater than 400 mg/m2have been associated with an increased risk of congestive heart failure (CHF) (Von Hoff, Ann Intern Med 1979). We are performing a retrospective analysis of approximately 325 patients with DLBCL who received treatment at Virginia Mason Medical Center from 2001-2011. Our objectives include the following: (1) to determine whether LVEF was measured by echocardiogram or MUGA scan prior to administration of anthracycline-based chemotherapy, (2) to establish whether the chemotherapy treatment regimen was modified based on LVEF values, and (3) to document the incidence of CHF in patients with DLBCL who did receive anthracycline-based chemotherapy. Patients were identified through a search of the Virginia Mason Cancer Registry. Specific data currently being collected through chart review include the following: age at diagnosis; Ann Arbor lymphoma stage; type of chemotherapy given; cumulative doxorubicin dose administered (mg/m2); LVEF measurement and modality used to assess LVEF; and incidence of CHF. We are also recording the number of CHF risk factors that patients possess, including male sex, obesity, hypertension, hyperlipidemia, prior cardiac disease, diabetes mellitus, smoking history, prior chemotherapy, radiation to the chest area, and other cardio-toxic exposures. Statistical analyses will include a Fischer’s exact or Chi-squared test to compare study groups and a Wilcoxon rank sum test to compare the number of CHF risk factors. A P value of less than 0.05 will be used to determine if an association is significant. In a preliminary sample of DLBCL patients (n = 50), 28 are men (56%). LVEF was measured in 40 patients (80%) prior to initiation of chemotherapy using echocardiogram (95%) and MUGA scan (5%). LVEF values were normal (55 – 75%) in 36 patients (90%), low (< 55%) in 3 patients (8%), and unknown in 1 patient (2%). Of the 36 patients with normal LVEF values, 30 received CHOP or R-CHOP regimens (83%), 2 received non-anthracycline chemotherapy (5%), 1 was treated by surgical excision alone (3%), 2 received no treatment (6%), and 1 patient’s treatment was unknown (3%). Of the 3 patients with initial low screening LVEF values, none had a prior history of CHF and all received R-CHOP (100%). Three patients did have CHF prior to treatment; however, only one received CHOP therapy. Of our initial 50 patients, 31 (62%) are alive and 2 (4%) were lost to follow-up. CHF was listed as a major contributor of death in 3 patients (6%). The median number of CHF risk factors did not differ significantly between patients who did develop CHF post-treatment and those who did not (4 vs. 2, P = 0.133). Our preliminary results suggest that the decision to administer an anthracycline-based chemotherapy regimen was not directly affected by echocardiogram or MUGA scan results. If these findings are reinforced at completion of our chart review, it may challenge the existing policy of routinely screening patients with DLBCL with echocardiograms or MUGA scans prior to initiation of treatment. Disclosures: No relevant conflicts of interest to declare.
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Diehl, Volker, Harald Stein, Michael Hummel, Raphael Zollinger, and Joseph M. Connors. "Hodgkin’s Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease." Hematology 2003, no. 1 (January 1, 2003): 225–47. http://dx.doi.org/10.1182/asheducation-2003.1.225.
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Abstract Hodgkin’s lymphomas belong to the most curable tumor diseases in adults. About 80% of patients in all anatomical stages and of all histological subtypes can be cured with modern treatment strategies. In spite of the great clinical progress, the pathogenesis of this peculiar lymphoproliferative entity has not been elucidated completely up until now. In Section I Drs. Stein, Hummel, and Zollinger describe the different pro-proliferative and antiapoptotic pathways and molecules involved in the transformation of the germinal center B-lymphocyte to the malignant Hodgkin-Reed-Sternberg cell. They use a comprehensive gene expression profiling (Affymetrix gene chip U133A) on B- and T-Hodgkin cell lines and state that the cell of origin is not the dominant determinant of the Hodgkin cell phenotype, but the transforming event. H-RS cells lack specific functional markers (B-T-cell receptors) and physiologically should undergo apoptosis. Why they do not is unclear and a matter of intensive ongoing research. In Section II Dr. Diehl summarizes the commonly used primary treatment strategies adapted to prognostic strata in early, intermediate and advanced anatomical stages using increasing intensities of chemotherapy (two, four, eight courses of chemotherapy such as ABVD) and additive radiation with decreased doses and field size. ABVD is without doubt the gold standard for early and intermediate stages, but its role as the standard regimen for advanced stages is challenged by recent data with time- and dose-intensified regimens such as the escalated BEACOPP, demonstrating superiority over COPP/ABVD (equivalent to ABVD) for FFTF and OS in all risk strata according to the International Prognostic Score. In Section III, Dr. Connors states that fortunately there is a considerably decreased need for salvage strategies in Hodgkin’s lymphomas since primary treatment results in a more than 80% tumor control. Nevertheless, a significant number of patients experience either a tumor refractory to therapy or an early or late relapse. Therefore, one of the continuing challenges in the care for Hodgkin’s lymphomas today is to find effective modes for a second tumor control. High-dose chemotherapy followed by autologous stem cell support has proved to be the treatment of choice when disseminated tumors recur after primary chemo- and or radiotherapy. Nodal relapses respond well to local radiation when they recur outfield of primary radiation without B-symptoms and in stages I–II at relapse. Allogeneic stem cell support needs further intensive evaluation in controlled studies to become an established alternative.
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Davies, Andrew. "Tailoring front-line therapy in diffuse large B-cell lymphoma: who should we treat differently?" Hematology 2017, no. 1 (December 8, 2017): 284–94. http://dx.doi.org/10.1182/asheducation-2017.1.284.
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AbstractAlthough there have been significant insights into the biology of diffuse large B-cell lymphoma (DLBCL) over recent years, progress in our therapeutic approach has been disappointing over the same timeframe. This is not for want of trying. In 2017, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the “gold standard,” despite all of our insights into cell-of-origin and other subgroups. We have traditionally used clinical risk factors to tailor our therapies and have tested intensification of chemotherapy with little success. We are now in an era of testing therapies according to the molecular phenotype of the individual’s tumor. Many phase 1/2 studies have looked at adding targeted agents to conventional R-CHOP with some promise. The phase 3 data are now starting to emerge. Are we ready yet to modify our standard of care and have we reached an era of precision medicine in DLBCL? The answer to this is “not yet.” The exception is perhaps patients with the newly defined World Health Organization category of high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, the so-called double- and triple-hit lymphomas. In these tumors there has been a move away from R-CHOP to more intensified regimens, however, has not been based upon rigorous prospective evaluation but review of retrospective datasets. This article will review the molecular subgroups of DLBCL, interventional strategies, and the outcomes of these interventions to date.
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Sharma, Anand, David Palmer, Hannah Brown, Sophie Merrick, Andrew Gogbashian, Nikhil Vasdev, Ben Pullar, and Marcia Hall. "A single center experience of the impact of treatment-related toxicity in the clinical outcomes of elderly patients with metastatic germ cell tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e16048-e16048. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16048.
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e16048 Background: Germ cell tumours (GCT) are predominantly a disease of the young, with < 10% of cases being diagnosed at ≥45 years. Platinum based chemotherapy is the gold standard in treating these patients. Data regarding outcomes and treatment toxicities in elderly patients is lacking. We studied the efficacy, toxicities and survival rates in a cohort of men diagnosed with GCT aged ≥45 years receiving chemotherapy in a metastatic setting. Methods: Data was collected retrospectively from 48 patient’s ≥45 years with GCT’s identified at Mount Vernon Cancer Centre, London. The histology, stage and international germ cell consensus (IGCC) risk classification was identified in all patients. Data was collected regarding chemotherapy regimens, number of cycles completed, toxicities and complications that led to treatment modifications or early cessation. Treatment toxicities were evaluated using the common terminology criteria for adverse events (ctCAE) grading. We then assessed progression free survival, relapse rates and overall survival (OS). Results: We identified 48 patients diagnosed with GCTs aged ≥45 years. The median age at diagnosis was 52 (range 45-70) and 75% of patients were aged ≥50. Classic seminoma and nonseminomatous GCTs were seen in 65% and 35% of patients, respectively. 75% of patients were ≥stage II at diagnosis. In total 29 patients received BEP, 4 EP, 7 Carboplatin AUC10, 2 Carboplatin AUC7 and 5 received POMBACE. 73 % (35/48) of patients experienced one or more complication/s from chemotherapy (15/48 ctCAE grade ≥3), of which the most common were neuropathies (27%), thromboembolism (10%) and tinnitus (10%). In 8 cases omissions or dose reductions had to be made and treatment delays occurred in 3 cases. Only 2 patients did not complete all intended cycles. Over 70% (35/48) of patients had an OS of > 5 years. One patient died during chemotherapy due to gastro-intestinal bleed. Conclusions: Survival rates in patients with GCTs aged ≥45 treated with chemotherapy are good with the majority achieving a > 5 year OS. Although age is not a prognostic factor, these patients are more prone to toxicities and have underlying comorbidities. This data will be of value to oncologists weighing up the risks versus benefits of treatment in this older cohort of patients in combination with similar studies.
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Sharma, Anant, Shabnam Bhandari Grover, Chinta Mani, and Charanjeet Ahluwalia. "Contrast enhanced ultrasound quantitative parameters for assessing neoadjuvant chemotherapy response in patients with locally advanced breast cancer." British Journal of Radiology 94, no. 1121 (May 1, 2021): 20201160. http://dx.doi.org/10.1259/bjr.20201160.
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Objectives: To evaluate the role of contrast-enhanced ultrasound (CEUS) quantitative parameters in predicting neoadjuvant chemotherapy (NACT) response in patients with locally advanced breast cancer (LABC). Methods: 30 patients with histologically proven LABC scheduled for NACT were recruited. CEUS was performed using a contrast bolus of 4.8 ml and time intensity curves (TICs) were obtained by contrast dynamics software. CEUS quantitative parameters assessed were peak enhancement (PE), time-to-peak (TTP), area under the curve (AUC) and mean transit time (MTT). The parameters were documented on four consecutive instances: before NACT and 3 weeks after each of the three cycles. The gold-standard was pathological response using Miller Payne Score obtained pre NACT and post-surgery. Results: A decrease in mean values of PE and an increase in mean values of TTP and MTT was observed with each cycle of NACT among responders. Post each cycle of NACT (compared with baseline pre-NACT), there was a statistically significant difference in % change of mean values of PE, TTP and MTT between good responders and poor responders (p-value < 0.05). The diagnostic accuracy of TTP post-third cycle was 87.2% (p = 0.03), and MTT post--second and third cycle was 76.7% (p = 0.004) and 86.7% (p = 0.006) respectively. Conclusion: In responders, a decrease in the tumor vascularity was reflected in the CEUS quantitative parameters as a reduction in PE, and a prolongation in TTP, MTT. Advances in knowledge: Prediction of NACT response by CEUS has the potential to serve as a diagnostic modality for modification of chemotherapy regimens during ongoing NACT among patients with LABC, thus affecting patient prognosis.
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Alatrash, Gheath, Matteo Pelosini, Rima M. Saliba, Gabriela Rondon, Weiqing Zhang, Sergio Giralt, Partow Kebriaei, et al. "Platelet Recovery Prior to Stem Cell Transplantation Predicts for Post- Transplant Outcomes in Patients with AML." Blood 112, no. 11 (November 16, 2008): 3000. http://dx.doi.org/10.1182/blood.v112.11.3000.3000.
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Abstract Achievement of complete remission (CR), with <5% blasts in bone marrow (BM), and peripheral blood platelet count >100K/ml remains the gold standard achievement of chemotherapy for AML. A significant fraction of patients proceed to HSCT with <5% blasts but without ever achieving platelet counts >100K/ml (CRp). It is possible that with new AML therapies, the proportion of patients in such a situation will increase. We hypothesized that achievement of CRp has a worse prognostic connotation than ‘classically’ defined CR, and sought to investigate this hypothesis in a cohort of AML patients transplanted between 7/1995 to 12/2007 at our institution (N=427). Methods: Patients were eligible for this analysis if they were in the following disease status at transplantation: compete remission (CR); first CR (CR1; <5% BM blasts and platelet count >100K/ml); second CR (CR2); first CRp (CRp1): patients that had <5% BM blasts but no platelet recovery following induction chemotherapy; primary induction failure (PIF): no CR with induction therapy (>5% and no platelet recovery); CRp2: patients that after first relapse achieved <5% BM blasts with salvage chemotherapy, but no platelet recovery; refractory: patients in first relapse that did not respond to salvage therapy (rel). A minimum of 30 days from the last day of chemotherapy to start of conditioning regimen elapsed for patients to be scored as CRp. Diagnosis were AML (n=376) or high-risk MDS (n=51). Conditioning included TBI-based (2%; n=8), oral/IV busulfan based-ablative regimens (61%; n=261), fludarabine/melphalan-based reduced intensity conditioning regimens (RIC) (36%; n=153), or other (1%; n=5). Fifty-eight percent of patients received matched sibling transplants (n=248), while 42% (n=179) received unrelated donor (UD) HSCT. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. ATG was administered to those who received grafts from UD. Results: Median age was 50 years (range 6–74); 51% of patients were 50 years or older (n=218); 55% were male (n=236). Disease status at HSCT was CR1 in 38% (n=164), CR2 in 24% (n=102), CRp1 in 11% (n=48), CRp2 in 7% (n=30); PIF 11% (n=47), and rel1 8% (n=36). Cytogenetics data were available for 90% (n=386) of patients. The proportion of poor-risk cytogenetics was comparable in patients who were in CR1 (39%) and CRp1 (44%), p=0.3, and in patients who were in CR2 (15%) and CRp2 (24%) p=0.2. Source of stem cells was BM in 41% of patients (n=174) and peripheral blood in 59% of patients (n=253). Ninety-six percent of patients engrafted. Fifty-one percent of patients have died (n=219); actuarial survival at 36-months was 49% for all patients. Thirty-one percent of patients (n=134) have progressed. Median follow-up among survivors is 42 months (range 3–131months). Non-relapse mortality (NRM) (figure 1), overall survival (OS) (figure 2), and hazard ratios for OS and NRM at 1-year (Table) favored patients who were transplanted in CR1 (vs. patients in CRp1 or PIF), or in CR2 (vs. CRp2 or rel1). Conclusion: In this cohort of patient with AML and MDS, patients in CR (CR1 or CR2) demonstrated significantly better OS and NRM compared to patients who underwent HSCT in CRp (CRp1 or CRp2). CRp conferred an intermediate prognostic status, better than refractory disease, but significantly worse than ‘classic’ CR. Our results suggest that achieving a CR prior to HSCT should remain the gold standard for patient in AML or MDS receiving allogeneic HSCT. Table. Hazard Ratios (HR) for non-relapse mortality (NRM) and overall survival (OS) at 1 year. NRM OS CR=complete remission; CRp=pathologic CR; PIF=primary induction failure. CR1 (n=164) Reference Reference CR2 (n=102) 1.4 (p=0.3) 1.3 (p=0.3) CRp1 (n=48) 2.4 (p=0.01) 2.4 (p=0.001) CRp2 (n=30) 1.7 (p=0.2) 1.9 (p=0.05) PIF (n=47) 3.7 (p=0.001) 3.6 (p=0.001) First relapse (n=36) 4.6 (p=0.001) 6.7 (p=0.001) Figure 1. NRM by Pre-Transplant Remission Status Figure 1. NRM by Pre-Transplant Remission Status Figure 2. OS by Pre-Transplant Remission Status Figure 2. OS by Pre-Transplant Remission Status
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Metges, Jean-Philippe, Jean François Ramée, Roger Faroux, Jean Yves Douillard, Marc Porneuf, Isabelle Cumin, Pierre-Luc Etienne, et al. "Efficacy and safety of FOLFIRINOX in patients with pancreatic metastatic cancer." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 248. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.248.
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248 Background: Efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) is one of the gold standard in metastatic pancreatic cancer as first-line therapy for patients with PS 0-1, good haematological and renal function and a subnormal bilirubin level. Pending approval, this treatment has been allowed in Brittany (B) and Pays de la Loire (PL) respecting these criteria. Methods: Observatory of Cancer B/PL is a network of 50 private/public cancer centers focused on good practice for cancer drugs use. Our aim is to evaluate the use of FOLFIRINOX between July 2010 and June 2013 in B/PL. Sex, age, successive chemotherapeutic regimens, toxicities, response rate, progression free survival (PFS) and overall survival (OS) have been studied. Results: Data of 79 patients, treated in 2010 (37%), in 2011 (54%) or early 2012 (9%) have been studied (44 men, median age 62 years [37-74]). 64 patients were metastatic when cancer was diagnosed. Principal site of metastases was liver (73%). 17 primary tumors were resected and 15 patients received an adjuvant chemotherapy (gemcitabine (n=14)).The median number of treatment cycles was 9 [1-24]. Objective response was observed in 29 patients (37%), disease stabilization in 18 patients (23%) and progression in 18 patients (23%). During treatment, 75% of patients had a dose adjustment and 30 % had one or more dose delays. 22 patients presented grade III/IV toxicity (almost neurotoxicity or haematologic). 42 patients had a second line of treatment (mainly gemcitabine) and 7 patients a third line. The median PFS and OS were respectively 174 days IC95% [125-216] and 309 days IC 95% [229-376]. Conclusions: Our preliminary results are relatively convenient with those of Conroy et al in 2011. A higher rate of response (37% vs 32%) has been found. Concerning PFS and OS, our results are clearly worst with 174 vs 195 days and 309 vs 338 days. Our results confirm the aggressiveness of this schedule with 75% of the patients requiring a dose adjustement. Analysis of all pancreatic metastatic patients treated by FOLFIRINOX in B/PL by the Observatory of Cancer allows to assess its good use in the real life.
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Anastasia, Antonella, Monica Balzarotti, Massimo Magagnoli, Michele Spina, Rita Mazza, L. Castagna, Andrea Nozza, et al. "Better Outcome with Tandem High DOSE CHEMOTHERAPY and AUTOLOGOUS STEM CELLS TRANSPLANT IN Relapsed/Refractory HODGKIN LYMPHOMA PATIENTS Which Reached COMPLETE REMISSION AFTER Ifosfamide- Gemcitabine-Vinorelbine Scheme (IGEV)." Blood 114, no. 22 (November 20, 2009): 1213. http://dx.doi.org/10.1182/blood.v114.22.1213.1213.
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Abstract Abstract 1213 Poster Board I-235 INTRODUCTION: Patients with relapse or refractory Hodgkin Lymphoma (HL) still have a poor prognosis. High dose chemotherapy (HDCT) with autologous stem cells transplant (ASCT) is the gold standard, while about 40-60% of patients treated can achieve a durable remission. Complete remission (CR) to salvage therapy is the issue for a better outcome after ASCT. IGEV chemotherapy is now emerging as the most powerful salvage scheme in terms of CR achieved, safety and stem cells mobilization. Tandem high dose chemotherapy and ASCT has been already reported as experimental approach in several non randomized studies which demonstrate its feasibility and low toxicity. AIM: To investigate the efficacy in term of FFP and OS of : To investigate the efficacy in term of FFP and OS of tandem high dose chemotherapy with ASCT compared to a single procedure, in the setting of HL patients which are in complete remission after IGEV. METHODS: From November 1997 to May 2007 121 patients were enrolled in a prospective trial with IGEV plus high dose chemotherapy with single or tandem ASCT. : From November 1997 to May 2007 121 patients were enrolled in a prospective trial with IGEV plus high dose chemotherapy with single or tandem ASCT. RESULTS: After IGEV, 56 patients reached complete remission. Main clinical characteristics: M/F: 30/26; median age: 31 years (15-70); refractory/relapsed: 18/38; median prior regimens: 1 (1-2); prior radiotherapy: 35; < 3/ >3 involved sites: 41/15. Of them 20 received a single procedure with BEAM whereas 36 received tandem ASCT (Melphalan 200 mg/m2 followed by BEAM within 3 months). No significant characterists emerged in the two populations in a match analysis. In our intention to treat analysis patients which received a single transplant have a relapse risk 3.3% higher than tandem group(C.I. 95%. 1.6.10; p value: 0.025). When we analyzed the program fulfilled, relapse risk was 2.13% higher ( C.I. 95%. 1.05, 4.34; p value: 0.035). No differences were seen in the OS, probably due to the eterogeneous salvage programs. : After IGEV, 56 patients reached complete remission. Main clinical characteristics: M/F: 30/26; median age: 31 years (15-70); refractory/relapsed: 18/38; median prior regimens: 1 (1-2); prior radiotherapy: 35; < 3/ >3 involved sites: 41/15. Of them 20 received a single procedure with BEAM whereas 36 received tandem ASCT (Melphalan 200 mg/m followed by BEAM within 3 months). No significant characterists emerged in the two populations in a match analysis. In our intention to treat analysis patients which received a single transplant have a relapse risk 3.3% higher than tandem group(C.I. 95%. 1.6.10; p value: 0.025). When we analyzed the program fulfilled, relapse risk was 2.13% higher ( C.I. 95%. 1.05, 4.34; p value: 0.035). No differences were seen in the OS, probably due to the eterogeneous salvage programs. CONCLUSION: Our data show the benefit of tandem ASCT in complete responders to IGEV salvage chemotherapy, in terms of FFP in a multivariate analysis, in patients with relapse or refractory HL. Furthermore, a randomized trial comparing tandem ASCT to a single course of ASCT after induction therapy could definitively demonstrate its usefulness. : Our data show the benefit of tandem ASCT in complete responders to IGEV salvage chemotherapy, in terms of FFP in a multivariate analysis, in patients with relapse or refractory HL. Disclosures No relevant conflicts of interest to declare.
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Panoskaltsis, Nicki, Eleni Pefani, Athanasios Mantalaris, Michael Georgiadis, and Efstratios Pistikopoulos. "Optimized Patient- and Leukemia-Specific Chemotherapy Protocols For The Treatment Of Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 4227. http://dx.doi.org/10.1182/blood.v122.21.4227.4227.
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Abstract Treatment for Acute Myeloid Leukaemia (AML) with chemotherapy may result in acute and long-term life-threatening complications due to drug toxicity. Only relatively few patient-and leukemia-specific factors are taken into consideration in current protocols and choice of treatment often depends on the treating physician’s experience. With the advent of novel treatments and large amounts of patient- and leukemia-specific genomic data, there is a clear need for a systematic approach to the design and execution of chemotherapy regimens. Mathematical modeling is a tool that can be used for the automation of chemotherapy treatment due to its advantages in systematically exploring extensive datasets in order to capture a system’s dynamics and subsequently provide better insight for process enhancement. An AML-specific model that combines the leukemia-specific actions of the cell cycle (i.e. drug target) with patient-specific pharmacology of the drugs (pharmacokinetics) was developed. Specifically, it simulates the response of patients with AML undergoing treatment with two standard chemotherapy protocols, one intensive and the other non-intensive: (a) Daunarubicin (DNR) and Cytosine Arabinoside (Ara-C) used in standard intravenous (iv) doses (DA – 3+7 or 3+10) and (b) low dose Ara-C (LDAC) administered subcutaneously (sc). Sensitivity analysis of the model identifies cell cycle times as the critical parameters that control treatment outcome. For model analysis, clinical data from 6 patients who underwent chemotherapy are used for the estimation of cell cycle time distribution. The patient data are comprised of disease characteristics (tumor burden, cell cycle times, normal cell population) as well as patient-specific characteristics (gender, age, weight and height). The estimated mean S-phase duration (Ts) is 15 hrs (range: 9-21 hrs) and mean whole cell cycle duration (Tc) is 47.5 hrs (range: 33-68 hrs). The estimated data reveal a clear relationship of cell cycle times to treatment outcomes. Specifically, low Ts duration combined with high Tc duration indicates worse treatment outcomes, whereas, the reverse combination is indicative of a good response to treatment. In order to improve effectiveness of AML therapy and reduction of toxicity, chemotherapy treatment is presented as an optimal control problem with the main aim of obtaining a treatment schedule which could maximize leukemic cell kill yet minimize death of the normal cell population in the bone marrow. By the end of treatment, the leukemic population should be reduced to a level of approximately 109 cells at which point BM hypoplasia is achieved. Out of the 6 patients studied, 2 patients had a successful treatment with leukemic hypoplasia achieved, 2 had a reduction of leukemic cells without achieving the hypoplasia target and 2 had disease progression on chemotherapy. The optimization algorithm is formulated and solved for all patients for both intensive and non-intensive treatment protocols with maximal and minimal thresholds set for efficacy and toxicity, respectively. For iv Ara-C, total drug administration is set between 50mg – 4000mg with infusion duration between 1 min to 24 hours. The window for DNR dose optimization is stricter due to potential toxic effects and the only independent variable is dose with 30mg – 90mg per infusion. For sc Ara-C, the maximum dose per day is 40mg and doses are permitted up to four times daily for a maximum period of 20 days. Optimization results obtained for the 6 patients indicate that continuous infusions are more effective for leukaemia cell kill than rapid infusions. For non-intensive chemotherapy, 40mg of Ara-C in continuous infusion over 10 days is better than daily divided doses with leukemic hypoplasia achieved for all patient case studies. For the intensive protocol, dose increase of DNR to 90 mg/m2 combined with Ara-C daily infusion is the optimal chemotherapy regimen. Ara-C doses differ between patients and the optimal dose range is between 200 to 250 mg/m2. In summary, this work presents the potential for improved treatment design in AML therapy, dependent on disease and patient characteristics, defined on a case-by-case basis. This design would provide the opportunity to personalize treatment protocols for gold standard intensive and non-intensive therapies as well as for novel drugs through the use of optimization methods. Disclosures: No relevant conflicts of interest to declare.
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Zervas, Konstantinos, Dimitra Mihou, Irini Katodritou, Anastasia Pouli, Chrisanthi H. Mitsouli, Athanasios Anagnostopoulos, Souzana Delimbasi, et al. "VAD-doxil vs.VAD-doxil Plus Thalidomide as Initial Treatment in Patients with Multiple Myeloma: A Multicenter Randomized Trial of the Greek Myeloma Study Group." Blood 108, no. 11 (November 16, 2006): 794. http://dx.doi.org/10.1182/blood.v108.11.794.794.
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Abstract Introduction: VAD-doxil and VAD-doxil plus thalidomide have already been separately evaluated, as initial cytoreductive treatment in multiple myeloma, in two previous clinical trials of our study group. Both regimens proved effective yielding overall (complete and partial) response rates of 61.3% and 74% respectively, while toxicity was acceptable in both studies. Aim of the study was to compare the efficacy and toxicity of these two regimens in the context of a multicenter randomized clinical trial. Patients and Methods: Patients randomized in arm A received vincristine 2mg IV, liposomal doxorubicin 40mg/m2 IV in a single dose on day 1, and dexamethasone 40mg PO daily for 4 days. The regimen was repeated every 4 weeks. Dexamethasone was also administered on days 15–18 of the first cycle. Patients randomized in arm B received VAD-doxil with continuous thalidomide 200 mg PO daily at bedtime. Response to treatment was the primary objective of the study and was evaluated after the completion of 4 cycles. Subsequently, patients were allowed to proceed to high dose chemotherapy or to receive two additional cycles of the same regimen. Response and toxicity were evaluated according to EBMT and NCI criteria respectively. Patients’ characteristics, response and toxicity rates were compared using two-independent- samples tests and x2 tests. Results: Between June 2002 and December 2005, 200 patients entered the study. Patients and disease features were equally balanced among the two groups. As of June 2006, 198 patients are evaluable for toxicity and 160, 80 in each arm, for efficacy. On an intention- to- treat basis, overall response rate was 66.3% and 81.3% in arms A and B respectively (p = 0.048). Neutropenia, thrombocytopenia, infections, mucositis, palmar-plantar erythrodysesthesia, deep venous thrombosis (DVT) and early mortality were not significantly different (p > 0.05) between arms A and B (13% vs. 15%, 8.5% vs. 10%, 7.5% vs. 5%, 5% vs. 4%, 6.3% vs. 5%, 3.8% vs. 9.5% and 6.3% vs. 5% respectively). Constipation, peripheral neuropathy, dizziness/somnolence, skin rash and edema were significantly higher (p < 0.05) in arm B compared to arm A (57% vs. 10%, 46% vs. 13.8%, 54% vs. 0%, 13% vs. 0%, 10% vs. 2% respectively). Conclusions: We added thalidomide to VAD-doxil which, at the time of trial design was considered the gold standard induction regimen in our Group for symptomatic patients with MM. VAD-doxil plus thalidomide compared to VAD-doxil alone, resulted in a higher response rate. The addition of thalidomide to VAD-doxil resulted in a higher rate of constipation, neuropathy and skin rash while the incidence of DVT was similar in both arms. The final analysis of this study will be performed in October 2006.
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Zhu, Andrew X., Yong Lin, David Raymond Ferry, Ryan C. Widau, and Abhijoy Saha. "Meta-analysis of surrogate endpoints for survival in patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitor-based regimens." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 483. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.483.
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483 Background: Overall survival (OS) remains the gold standard for demonstrating clinical benefit in advanced hepatocellular carcinoma (HCC). While surrogate radiology-based endpoints for OS, such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in the field of oncology, they remain controversial in the setting of HCC where antiangiogenic agents were the mainstay of treatment until recently. Immune checkpoint inhibitors (CPIs) as monotherapy or in combination have shifted the treatment paradigm in HCC. We investigated the surrogacy of radiology-based endpoints from CPI clinical trials in advanced HCC. Methods: Study level data were collected for disclosures published in EMBASE, PubMed, Clinicaltrials.gov and conference abstracts. Keywords used included (abbreviated here): immune CPIs, advanced or metastatic HCC and ORR, PFS and OS. Key inclusion criteria included: Phase I, II and III trial data, and patients with advanced or metastatic HCC who received CPI monotherapy or in a combination regimen. The endpoints investigated were median OS (mOS), median PFS (mPFS) and ORR (RECIST v1.1). A weighted Pearson correlation coefficient, with weights corresponding to the number of patients in the different treatment arms of the trials, was calculated between ORR/mOS, ORR/mPFS and mPFS/mOS in all arms, arms that included only patients with Child-Pugh A liver function, and arms in the first-line therapy setting. 95% confidence intervals (CIs) based on the empirical bootstrap re-sampling method are also reported. Results: Eighteen clinical trials (8 randomized trials and 10 multi-cohort trials) published between 2017 and 2021, including 3,246 patients across 32 treatment arms, were selected for inclusion in this meta-analysis. Ten trials included CPI monotherapy arms, 5 trials included CPI + TKI arms, 4 trials included CPI + anti-angiogenic monoclonal antibody arms, and 2 trials included CPI + CPI arms. There was 1 CPI + chemotherapy arm and 1 CPI + CPI + TKI arm in separate trials. Weighted Pearson correlation coefficients and corresponding 95% CIs are presented in the table. Conclusions: Our analysis suggests ORR/mOS, ORR/mPFS, and mPFS/mOS are positively correlated, with ORR/mPFS more strongly correlated compared to the other pairs, in patients with advanced HCC who were treated with CPI-based regimens. [Table: see text]
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Pompa, Alessandra, Anna Ines Gregorini, Francesca Guidotti, Maria Cecilia Goldaniga, Francesca Gaia Rossi, Riccardo Marcolin, Luca Baldini, and Agostino Cortelezzi. "Outpatient Stem Cell Mobilization with Intermediate-Dose Cyclophosphamide Is a Safe and Effective Procedure." Blood 128, no. 22 (December 2, 2016): 5734. http://dx.doi.org/10.1182/blood.v128.22.5734.5734.
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Abstract Background In younger and fit multiple myeloma (MM) patients (pt), autologous stem cell transplantation (ASCT) remains the gold standard treatment. Mobilization chemotherapy is usually administered in an inpatient regimen and Cyclophosphamide (CY) at different doses is the most used chemoterapy for collecting peripheral blood stem cells (PBSC) in MM. Clinical trials have demonstrated that intermediate dose CY (3 and 4 g/m2, ID-CY) combined with G-CSF, is an efficient mobilizing regimen with less toxicity compared with high dose CY (7 g/m2, HD-CY) in term of neutrophil recovery, thrombocytopenia, need of transfusions and IV antibiotics. (Fitoussi et al, BMT 2001; Goldschmidt et al, BMT 1996). Objective To evaluate the safety of mobilization therapy administered in an outpatient regimen, with the prospect to lower costs and minimize patient inconvenience, maintaining an optimal yield. Methods 92 pt with newly diagnosed MM underwent outpatient stem cell mobilization between 2002 and 2016 with CY 3 g/m2 (82%) or 4 g/m2 (18%) + G-CSF after induction therapy with bortezomib-based (79%) or VAD-like (21%) regimens. No antibiotics prophylaxis was routinely used. Day 0 was defined as the CY infusion day. CY was administered in 2-4 consecutive 1h infusions (depending on total dose). Hyper-hydration (3.5/4 l), antiemetics and the uroprotectant Uromitexan were began IV 1 hour before CY infusion. Subsequently, Uromitexan was continued at home orally in the next 12h. Furthermore, the patient was advised to drink 2.5/3 l of water in the next 24h. G-CSF 10 mcg/Kg was started by day +5 and continued until completion of apheresis. Blood count was monitored at day + 4 and daily from day +7. CD34+ cells were counted on peripheral blood by day 7; apheresis was started at leukocyte rise and with a value of at least 20 CD34+/μl. Number of apheresis depended on the number of CD34+ cells collected to obtain al least 4x106 CD34+/Kg. Results Median age at diagnosis of was 56y (range 34-68). MM isotype was IgA, IgG and micromolecular respectively in 18%, 58% and 24%. Prior MGUS was present in 37 cases (43%). LDH was elevated in 7 pt (11%), whereas ISS was 1/2/3 in 47%/30%/23%. Bone disease was detectable in 74% of pt, with 56% having 3 or more osteolysis. Median bone marrow plasma cell at diagnosis was 60% (range 10-95%). Pt received induction with bortezomib-based regimens (79%) or chemoterapy, mostly VAD (21%). 8 pt (9%) required second line therapy before mobilization. Response prior of mobilization was CR/sCR in 15%, VGPR in 59%, PR in 24%, and SD in 2%. Stem cell collection was successful in 98% of pt, with a median CD34+ harvest of 9.8x106/Kg. Chemotherapy was very well tolerated. Most frequently observed adverse events (AEs) were nausea and vomiting of grade 1-2. 2 pt experienced cystitis (one grade 1, one grade 2), 2 pt infections, 2 pt hyperthermia regressed rapidly without therapy, 1 patient diarrhea. 3 pt had neurological symptoms: in 2 cases they were aspecific (headache, instability); the other case presented a sudden appearance of 7th cranial nerve deficit at the end of mobilization chemotherapy infusion with negative imaging and successively regressed in few hours, interpreted as transient ischemic attack not correlated with Cy. Only 2 patient required hospitalization for AEs: 1 patient for fever grade 3 without microbiological findings, rapidly regressed with IV antibiotics; the second one for 7th cranial nerve deficit. These were the only grade 3 AEs, no grade 4 AEs verified. There were no other significant AEs related to chemotherapy. All pt except 2 proceeded to stem cell harvest and reached CD34+ target, but 5 pt required administration of Plerixafor on demand. The 2 pt not reaching CD34+ target successfully mobilized afterwards, 1 with different chemoterapy and the other with G-CSF and Plerixafor. After mobilization, 88 pt proceeded to single (45%) or double (55%) ASCT. Conclusion In conclusion, outpatient mobilization with ID-CY appears to be an efficient and safe procedure, with minimal and manageable side effects and low rate of hospitalization. Outpatient mobilization could ameliorate the quality of life of pt and reduce costs, avoiding or minimizing the hospitalization rate, without compromising the safety profile and the success of PBSC collect. Disclosures No relevant conflicts of interest to declare.
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Freeman, Karoline, Martin Connock, Ewen Cummins, Tara Gurung, Sian Taylor-Phillips, Rachel Court, Mark Saunders, Aileen Clarke, and Paul Sutcliffe. "Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion." Health Technology Assessment 19, no. 91 (November 2015): 1–322. http://dx.doi.org/10.3310/hta19910.
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Background5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.ObjectivesTo systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.Data sourcesWe searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.MethodsTwo reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan–Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.ResultsA total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were –18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU + folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £20,000 per QALY.LimitationsQuality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.ConclusionsUsing a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.FundingThe National Institute for Health Research Health Technology Assessment programme.
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Gutiérrez-García, Gonzalo, Luis Colomo, Neus Villamor, Leonor Arenillas, Antonio Martínez, Mireia Camós, Marina Diaz-Beyá, et al. "No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma." Blood 112, no. 11 (November 16, 2008): 3615. http://dx.doi.org/10.1182/blood.v112.11.3615.3615.
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Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood2004;103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies. Complete response CR (%) 5-years OS (%) CT R-CT CT R-CT *p<0.002 R-CT vs. CT All cases (n=230) 59 79* 46 70* Primary nodal (n=148) 54 78* 34 71* Primary extranodal (n=82) 68 78 70 69 Figure Figure
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Miller, Tamara P., Yimei Li, Marko Kavcic, Andrea B. Troxel, Yuan-Shun V. Huang, Lillian Sung, Todd A. Alonzo, et al. "Accuracy of Adverse Event Ascertainment in Clinical Trials for Pediatric Acute Myeloid Leukemia." Journal of Clinical Oncology 34, no. 13 (May 1, 2016): 1537–43. http://dx.doi.org/10.1200/jco.2015.65.5860.
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Purpose Reporting of adverse events (AEs) in clinical trials is critical to understanding treatment safety, but data on AE accuracy are limited. This study sought to determine the accuracy of AE reporting for pediatric acute myeloid leukemia clinical trials and to test whether an external electronic data source can improve reporting. Methods Reported AEs were evaluated on two trials, Children’s Oncology Group AAML03P1 and AAML0531 arm B, with identical chemotherapy regimens but with different toxicity reporting requirements. Chart review for 12 AEs for patients enrolled in AAML0531 at 14 hospitals was the gold standard. The sensitivity and positive predictive values (PPV) of the AAML0531 AE report and AEs detected by review of Pediatric Health Information System (PHIS) billing and microbiology data were compared with chart data. Results Select AE rates from AAML03P1 and AAML0531 arm B differed significantly and correlated with the targeted toxicities of each trial. Chart abstraction was performed on 204 patients (758 courses) on AAML0531. AE report sensitivity was < 50% for eight AEs, but PPV was > 75% for six AEs. AE reports for viridans group streptococcal bacteremia, a targeted toxicity on AAML0531, had a sensitivity of 78.3% and PPV of 98.1%. PHIS billing data had higher sensitivity (> 50% for nine AEs), but lower PPV (< 75% for 10 AEs). Viridans group streptococcal detection using PHIS microbiology data had high sensitivity (92.3%) and PPV (97.3%). Conclusion The current system of AE reporting for cooperative oncology group clinical trials in pediatric acute myeloid leukemia underestimates AE rates. The high sensitivity and PPV of PHIS microbiology data suggest that using external data sources may improve the accuracy of AE reporting.
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Ramos-Torres, Guillermo, Marcio Marcio Concepción-Zavaleta, Sofía Ildefonso-Najarro, Esteban Plasencia-Dueñas, Jhean Gonzãles-Yovera, Carlos Alcalde-Loyola, Luis Concepción-Urteaga, et al. "ODP336 Nephrogenic Diabetes Insipidus and Fanconi Syndrome Induced by Ifosfamide in a Patient with Femur Osteosarcoma. A Case Report." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A502—A503. http://dx.doi.org/10.1210/jendso/bvac150.1045.
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Abstract Background Fanconi syndrome and diabetes insipidus are rare adverse effects of ifosfamide. They usually present with high cumulative doses of this medication. They are mainly related to type II proximal renal tubular dysfunction. These complications typically present with severe polydipsia and polyuria accompanied by glycosuria, proteinuria, and some electrolyte abnormalities including hypokalemia, hypophosphataemia, and non-anion gap metabolic acidosis. Clinical case: A 15-year-old male with, a diagnosis of metastatic osteoblastic osteosarcoma in the right distal treated with ifosfamide three years prior to this hospitalization, was admitted to the emergency department complaining of 3 episodes of vomiting, 6 days history of increase volume of the right lower limb and fever. On admission, blood pressure of 80/50 mm Hg, heart rate of 110 beats / minute, respiratory rate of 30 breaths / minute, axillary temperature of 38.3 ° C. It was evident phlogosis at level of the proximal third of the right lower limb. CBC revealed pancytopenia (WBC 5 x10 9 L, Hb 6.8 g/dL, platelets 25×10 3 /mm 3) and ABG and CMP were compatible with mild metabolic acidosis normal AG (pH 7.285, K 1.9 meq / L, Na 156 meq / L, lactate: 0.9 meq / L, HCO3: 17 meq / L). A diagnosis of sepsis was made and the patient was started on meropenem 2g IV every 8 hours, vancomycin 1 g IV every 12 hours, filgastrim 120 ug/daily and one unit of packed RBC. Patient improved after 5 days over the course of his hospitalization. However, on the 18 th day after his hospital admission, he developed a new episode of polyuria, associated with hypocalcemia (7 mg/dL), hypokalemia (2 mEq/L), hypomagnesemia (0.95 mg/dL), hypophosphatemia (0.9 mg/dL) and metabolic acidosis (pH 7.2, bicarbonate 15 mEq/L). Urine analysis revealed glucosuria and proteinuria. Desmopressin test did not showed increase urinary osmolarity thus nephrogenic diabetes insipidus and Fanconi syndrome were diagnosed due to the multiple laboratory abnormalities and sign/symptoms. Patient received electrolyte replacement and ifosfamide was stopped from his chemotherapy regimen. After this, patient recovers and he was discharge at 25 th day of his admission. Conclusion : Ifosfamide causes tubular cell dysfunction leading to both nephrogenic diabetes insipidus and Fanconi syndrome. These complications might event present several years after receiving this chemotherapeutic agent. Full electrolyte repletion and hydration are the gold standard for management The present case report emphasizes the importance of the prevention of nephrotoxicity associated with ifosfamide, since its presentation could increase poor outcomes in patients receiving chemotherapy regimens that include ifosfamide. Presentation: No date and time listed
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Kuznetsov, Julie Lawrence, Kathryn Bailey, Pacharintra K. Bombach, Stacey Carmichael, Xuemei Chen, Maja Lichstein Herberg, Terri Owen, Jorge Wilson, and Douglas W. Blayney. "Real-time extraction of breast cancer treatment process and outcome measures from an EPIC electronic health record (EHR)." Journal of Clinical Oncology 31, no. 31_suppl (November 1, 2013): 1. http://dx.doi.org/10.1200/jco.2013.31.31_suppl.1.
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1 Background: In 2011, Stanford Cancer Institute (SCI) clinical leadership began process improvements to enhance patient satisfaction and quality of care. To measure impacts, unnecessary care variation, and outcomes, we recently developed an informatics infrastructure utilizing data from our EHR (epic modules: BEACON, Cadence, OpTime). We report successful initial efforts including real-time cohort identification (comparing with “gold standard” registry data), and improvements in time to treatment. Methods: A cohort of 1,692 patients was defined by 3 criteria: newly evaluated at SCI, AND received treatment [surgery, chemotherapy (chemo), or radiation (XRT)] at SCI, AND had a breast cancer related ICD-9 code. We analyzed data by fiscal year (FY), starting September, 2010 to FY13 year-to-date. “Time to treatment (Rx)” was measured as the interval between first EHR time stamp for SCI patient contact and Rx date. We used discrete data from the BEACON staging module to create sub-cohorts by stage, and used BEACON protocols to identify chemo regimens. Our cohorts were compared with SCI tumor registry data, and presented in a dynamic Qlikview dashboard. Results: 98% of the EHR-defined cohort matched a similarly defined tumor registry cohort. We detected the effect of process improvements (including scheduling a visit on first contact, coordinating among surgical specialties, outside records available pre-visit, etc.), which resulted in an accelerated time to Rx (Table). Discrete BEACON stage is available for 7% of these 1692 patients. The methodology is scalable and has been successfully replicated in GI and thoracic cohorts. Conclusions: Our work demonstrates utility of EHR data to track process improvements. Uniform use of the BEACON staging module will facilitate variation analysis across cancer types and stages, and allow us to explore variation within modalities (chemo, surgery, XRT). We will analyze associated costs and intermediate clinical outcomes (e.g., unplanned emergency visits and hospitalizations) to inform care pathway choice. [Table: see text]
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Falorio, Simona, Francesco Angrilli, Francesca Fioritoni, Stella Santarone, and Giuseppe Fioritoni. "Risk and Response Adapted Treatment of Primary Mediastinal B-Cell Lymphoma (PMBCL): Single Institutional Experience." Blood 112, no. 11 (November 16, 2008): 4938. http://dx.doi.org/10.1182/blood.v112.11.4938.4938.
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Abstract Background: PMBCL accounts for nearly 2% of all non Hodgkin lymphoma. The most effective treatment of this disease is unknown. In retrospective studies third generation chemotherapy regimens, namely MACOP-B or VACOP-B, plus radiotherapy achieved better results in comparison with conventional CHOP. Moreover, the value of the addition of rituximab (R) to CHOP or MACOP-B in PMBCL is not well-known today. The purpose of this study is to evaluate the results of our experience in the treatment of PMBCL. Methods: Between 1/2000 and 1/2008, 25 untreated patients (pts) with PMBCL have been admitted in our institution. Disease evaluation was performed with whole-body computed tomography at diagnosis, after 3–4 courses or after 2 months of chemotherapy and at the conclusion of treatment. At early restaging, pts who obtained at least a partial remission (PR) completed planned treatment, while unresponsive pts started high dose sequential chemotherapy (HDSC) (2 courses of APO, 2 courses of DHAP, cyclophosphamide 7gr/m2, methotrexate 8gr/m2, etoposide 2gr/m2) followed by autologous stem cells transplantation (ASCT). In a first time, the planned treatment generally consisted of third generation chemotherapy (PROMACE-CYTABOM in 5 pts and MACOP-B in 1 pt) plus involved field radiotherapy (IFRT) (36 Gy). Another patient with high risk disease (stage IVB, aaIPI 3) received front-line HDSC plus ASCT. One patient aged 16 years was treated according NHL97-AIEOP pediatric protocol (drugs total dose mg/m2, course A: iphosphamide 4000, methotrexate 5000, cytarabin 300, etoposide 200, vincristine 1,5. Course B: cyclophosphamide 1000, methotrexate 5000, daunomycin 50, vincristine 1,5. Course C: cytarabin 12000, etoposide 500, vindesine 3) plus IFRT (36 Gy). Subsequently, for the remaining 17 pts, planned treatment consisted of R-CHOP chemo-immunotherapy (CHOP21 in 4 cases and CHOP14 in 13 cases) plus IFRT (36 Gy). Retrospectively, we evaluated the response rate, overall survival (OS) and disease free survival (DFS). Results: 5 pts were male and 20 female (M/F ratio: 0,25); median age was 32 years. Stage I–II was present in 20 pts and stage III–IV in 5; aa-IPI was 0–1 in 20 pts and 2–3 in the remaining 5. Fifteen pts (60%) had B symptoms at the time of diagnosis. After early restaging, 21 pts (84%) showed at least a PR. The other 4 pts, who were treated with third generation chemotherapy (1/6, 17%) or R-CHOP (3/17, 18%) and who were early unresponsive, received treatment intensification with HDSC followed by ASCT in 2 cases. At present, 1 patient died of sepsis during MACOP-B, 2 pts are still under treatment and 22 pts completed treatment. We obtained a complete remission (CR) in 19 pts (86%) and a PR in 2 pts (9%). One of the last 2 pts achieved CR after HDSC plus ASCT. Overall, 5 pts received treatment intensification (4 after early restaging and 1 after treatment completion). With a median follow-up of 44 months, OS was 87% and DFS of the 20 CR pts was 100%. Two pts (1 with PR, 1 with unresponsive disease) died of progressive lymphoma. No difference in response and outcome was seen between third generation chemotherapy and R-CHOP. Conclusions: various chemo-radiotherapic combinations have been used successfully in the treatment of PMBCL. Waiting for prospective studies aimed to define a gold standard treatment, we think that our response-adapted treatment modality is an effective approach for inducing durable response in the majority of pts with PMBCL.
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Widiarta, Ida Bagus Wisnu, Anbiya Khairul Umam, and I. Putu Santhi Dewantara. "Kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin: tinjauan pustaka." Intisari Sains Medis 11, no. 3 (December 1, 2020): 1258–63. http://dx.doi.org/10.15562/ism.v11i3.686.
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Background: Malignancies are one of the diseases with the most sufferers, almost all country in the world has a number of these diseases. Cisplatin-based chemotherapy regimens have long been the gold standard in the treatment of various soft tissue malignancies. Despite many beneficial cisplatin features, it also has serious side effects, which are nephrotoxicity, neurotoxicity, and ototoxicity. This literature study aims to theoretically review the role of kenpaullone (CDK2 Inhibitor and GSK-3? Inhibitor) as an autoprotective agent in cisplatin-based chemotherapy patients.Methods: The literature review approach is used in this study. Sources of reading come from relevant and appropriate journals and books from PubMed and Google Scholar.Results: Cisplatin is thought to selectively damages the outer hair cells within the organ of Corti, spiral ganglion cells, and cells within the stria vascularis. It is reducing the formation of free radicals as otoprotective strategies by maintaining glutathione levels and antioxidant activity. Kenpaullone provided significant protection against cisplatin-induced ototoxicity when delivered by tran tympanic injection in zebrafish, mice, and rats. Kenpaullone has proven to directly inhibit cyclin-dependent kinase 2 (CDK2) and Glycogen synthesis kinase-3, thereby attenuating cisplatin-induced mitochondrial ROS production caspase 3/7-mediated cell death. Cisplatin can cause ototoxicity in the manifestation of hearing loss; thus, an otoprotector is needed to prevent this side effect. Kenpaullone is a CDK2 inhibitor and GSK-3 inhibitor that can reduce damage to outer hair cells induced by cisplatin to prevent ototoxic hearing loss.Conclusion: The results of this study indicate that various literature studies show that kenpaullone (CDK2 Inhibitor and GSK-3? Inhibitor) can be used as an autoprotective agent in cisplatin-based chemotherapy patients. Latar Belakang: Keganasan merupakan salah satu penyakit yang memiliki jumlah pasien terbanyak, hampir seluruh negara di dunia memiliki jumlah penderita penyakit tersebut. Kemoterapi berbasis cisplatin telah lama menjadi baku emas untuk terapi pada beberapa keganasan jaringan lunak. Selain memberikan banyak keuntungan, cisplatin juga menimbulkan efek samping yang berat seperti nefrotoksik, neurotoksik, dan ototoksik. Studi tinjauan pustaka ini bertujuan untuk meninjau secara teoritis peran kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin.Metode: Dalam penulisan ini digunakan metode tinjauan pustaka. Sumber bacaan berasal jurnal-jurnal dan buku-buku yang relevan dan sesuai dari PubMed maupun Google Scholar.Hasil: Diduga bahwa cisplatin secara selektif merusak bagian sel luar disertai organ korti, sel ganglia spiral, dan sel dengan stria vaskularis. Strategi otoprotektif termasuk menurunkan pembentukan radikal bebas dengan menjaga level gluthione dan aktivitas antioksidan. Kenpaullone memberikan efek protektif signifikan terhadap ototoksisitas akibat terapi cisplatin ketika dinjeksikan secara transtimpani pada ikan zebra, dan tikus. Kenpaullone terbukti secara langsung menginhibisi Cyclin-Dependent Kinase 2 (CDK-2) dan Glycogen Synthesis Kinase-3 (GSK-3), menurukan produksi ROS mitokondria yang diinduksi oleh cisplatin serta caspase 3/7 yang memediasi kematian sel. Sehingga hal tersebut dapat mencegah terjadinya gangguan pendengaran akibat ototoksik.Kesimpulan: Hasil tinjauan pustaka ini menunjukkan bahwa berbagai studi literatur menunjukkan bahwa kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) dapat dipergunakan sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin.
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Tchekmedyian, Vatche, Alan Loh Ho, Lara Dunn, James Vincent Fetten, David G. Pfister, Stephanie Lobaugh, Zhigang Zhang, et al. "A retrospective analysis of cisplatin dosing strategies when used with radiation on outcomes in head and neck squamous cell carcinoma of the oropharynx." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6079. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6079.
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6079 Background: Cis is the gold standard radiosensitizer for CRT to treat head and neck cancer. Prospective trials have required that cis be administered early in the week (Mon/Tues) to optimize radiosensitization without evidence to support this practice. This retrospective analysis considers the impact of cis day of week (DOW) administration and other variables on OPSCC pt outcomes. Methods: We reviewed OPSCC cases treated with primary CRT at our center. Pts treated with non-cis or induction chemotherapy were excluded. Data collected includes age, DOW (Mon/Tues vs Wed/Thurs/Fri), smoking status, total dose (TD) of cis (≤200mg/m2 vs > 200mg/m2), single dose (SiD) [100mg/m2 x1 day] vs split dose (SpD) [50mg/m2 x2 days] administration, T stage (0-2b vs 2c-3), N stage (0-2b vs 2c-3), overall survival (OS) (from start of RT), local/regional/distant failure, KPS and HPV/p16 status. Univariate Cox proportional hazards regression was used to analyze OS and multivariate Cox proportional hazard model investigated the relationships between OS and cis dosing variables while controlling for other factors. Results: 745 pts with OPSCC were treated with CRT from 7/31/2001-2/7/2014. 459 used cis based regimens and were included. Median age at start of RT was 55. 311 pts (67.8%) received SpD, 124 (27%) received SiD, 8 (1.7%) received weekly cis and 16 (3.5) received mixed cycles. 269 (58.6%) received ≤200mg/m2. 232 (50.5%) were HPV/p16 positive, 40 (8.7%) were negative and 187 (40.7%) were unknown. Median f/u was 7.9yrs (1.8m -18.9yrs). There were 92 (20%) deaths, and 75 (16.4%) recurrences (local/regional and distant) with 44 (9.6%) competing events. In univariate analysis, age, N stage, T stage, KPS and HPV/p16 status were significantly associated with OS, while DOW, TD, and SiD/SpD were not. In multivariate analysis (MVA), none of the associations between cis dosing and OS were significant (although MVA was limited by low number of events and total variables included). Conclusions: This retrospective analysis suggests that the DOW cis is given has no impact upon CRT outcomes for OPSCC pts. SpD cis represents an alternative administration approach.
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Kasireddy, Vineela. "Double Hit Lymphomas: Role of Immunohistochemistry in the Era of Florescent in-Situ Hybridization." Blood 128, no. 22 (December 2, 2016): 5405. http://dx.doi.org/10.1182/blood.v128.22.5405.5405.
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Background Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. A subset of DLBCL patients with translocations involving MYC and BCL2 genes, called "Double-hit" lymphoma (DHL), are being identified to have poor prognosis after standard chemotherapy. Fluorescent in situ hybridization (FISH) technique which can identify these gene mutations is the gold standard for diagnosis of DHL. Immunohistochemistry (IHC) is a rapid and inexpensive test that can identify abnormal protein expression of these mutated genes. Two studies thus far have shown that MYC IHC can be used as a screening test to identify DHL cases with sensitivities of 74% and 100%, both multi-center studies conducted at university hospitals. We conducted this study at a single large community hospital to determine if these results can be generalized to our institution. Objective Our primary objective was to determine the association between protein and genetic expression of MYC and BCL2 in cases of de novo DLBCL by comparing the results of IHC and FISH. Our secondary objectives were to determine if MYC IHC could be used as a screening test to determine DHL status, to determine if the double hit biology is associated with any clinic-pathological features which might allow for risk stratification of patients and to determine the prevalence of DHL in our cohort of DLBCL patients. Methods Twenty-two patients who were diagnosed with primary DLBCL from February 2015 to February 2016 at Abington Hospital (AH) Jefferson Health were identified after applying exclusion and inclusion criteria. Clinico-pathological data was obtained by review of electronic medical records and biopsy specimens for IHC and FISH were obtained from the Department of Pathology at AH. The FISH test was performed by Quest Diagnostics™ and IHC was performed by the Chair of the Department of Pathology at our institution. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 20.0 (Armonk, NY: IBM Corp). Results Double hit gene rearrangements by FISH were detected in 3/22 (13.6%) patients. MYC IHC was positive in 8/22 (36.3%) cases, and 3 of these 8 cases (37.5%) were FISH positive. Sensitivity, specificity and concordance of MYC IHC as a screening tool were 100%,73.6% and 72.27%, respectively. BCL2 staining was positive in 19/22 (86.3%) cases, and only 3 of the 19 cases (15.7%) were FISH positive. 5/22 (22.7%) cases were positive for both MYC and BCL2 by IHC (double protein expresser status) and 3 of these 5 (60%) cases were positive for DHL status by FISH. DHL biology did not show an association with any clinico-pathological parameters including age, elevated serum Lactate dehydrogenase, R-IPI (Revised International Prognostic Index) score, ECOG performance status, extra-nodal disease and cell-of-origin sub-type. Conclusion The association between MYC IHC and FISH in our study was not statistically significant but showed a trend towards association. Given that sensitivity of MYC in our study was 100%, we propose that it can be used as an effective screening test if similar results can be validated in larger studies. Our study supports the practice of routinely testing for MYC and BCL2 status in all cases of DLBCL, irrespective of clinical features of the disease, to identify the high-risk DHL subset of patients, who can be candidates for more intense newer chemotherapy regimens and for prognostic purposes Disclosures No relevant conflicts of interest to declare.
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Cahen, Viviane C., Yimei Li, Caitlin W. Elgarten, Amanda M. DiNofia, Jennifer J. Wilkes, Lena E. Winestone, Yuan-Shung V. Huang, et al. "Using Administrative Data to Identify Relapse and Hematopoietic Stem Cell Transplantation (HSCT) in Children with Acute Lymphoblastic Leukemia (ALL): Validation at Two Centers and Incidence Estimation in a National Cohort." Blood 132, Supplement 1 (November 29, 2018): 624. http://dx.doi.org/10.1182/blood-2018-99-114228.
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Abstract Administrative databases can be used to study outcomes including patients outside of clinical trials and have been used to identify relapse and HSCT in adult and adolescent/young adult leukemia populations. However, there are no published studies using validated billing and diagnostic codes to identify timing of relapse or HSCT in children with ALL. Published approaches are limited to relapses occurring after cessation of therapy, but a substantial proportion of pediatric ALL relapses occur on therapy. We hypothesized HSCT and early and late relapses could be detected accurately in a previously assembled cohort of children with ALL (Fisher 2014 Med Care), using pharmacy billing and ICD-9 diagnosis and procedure codes. We present our methods, validated at two large freestanding children's hospitals, and incidence estimates of relapse or HSCT as first events in a national cohort. The Pediatric Health Information System (PHIS) cohort included patients aged 0-21 admitted between 1/1/2004 and 12/13/2013, previously identified with de novo ALL. We reviewed daily inpatient pharmacy, diagnosis, and procedure codes for patients in the PHIS ALL cohort from the Children's Hospital of Philadelphia (CHOP; 2004-2013) and Texas Children's Hospital (TCH; 2007-2013). Events were captured until the first of 5 years from diagnosis or last day of PHIS data. Relapses were identified using ICD-9 diagnosis/procedure codes and PHIS pharmacy codes (Figure 1A) correlating with relapse regimens. Manual review of daily PHIS data was performed for second-line chemotherapy at any time, reinduction-style chemotherapy365 days after diagnosis, or a relapsed ALL ICD-9 diagnosis code (204.02). HSCTs were identified using ICD-9 procedure and PHIS pharmacy code patterns consistent with conditioning (Figure 1B). We reviewed electronic medical records (EMR) for patients with do novo ALL from CHOP and TCH for all relapses and HSCTs as the gold standard. Demographics were evaluated by hospital and data source using chi-square tests. We calculated sensitivity and positive-predictive value (PPV) of PHIS-defined events compared to the EMR gold standard at the patient level and only considered the first relapse and HSCT per patient. PHIS events were considered valid if the date was within ±14 days of the EMR. We estimated 5-year incidences of relapse and HSCT as first events for the entire PHIS cohort, infants (<1 year at diagnosis), and high-risk ALL (receipt of daunorubicin in Induction). Of 395 patients in the CHOP EMR cohort, 362 matched with the PHIS ALL cohort. The TCH EMR cohort had 410 patients, matching 329 from PHIS. Age, sex, and Down syndrome were similar (Table 1). CHOP patients were more likely to be Black, and race distribution within each hospital was similar by data source. Fewer CHOP patients were Hispanic, and more had missing ethnicity. Fewer TCH patients were missing ethnicity regardless of data source, though PHIS had a higher proportion of missing data. Proportions of children with high- and low-risk B-ALL, T-ALL, infant ALL, and Induction daunorubicin were similar. Government primary insurance in the first admission was more common at TCH. At CHOP, 39 relapses were identified in PHIS, and 45 by EMR (sensitivity 85.7%, PPV 100%). At TCH, 30/31 relapses were correctly identified in PHIS (sensitivity 96.6%, PPV 100%). Our PHIS algorithm identified 38 CHOP patients who underwent HSCT during the study period and 34 at TCH. All matched the EMR, with 100% sensitivity and PPV for both hospitals. Table 2 shows five-year incidences of relapse and HSCT in the entire PHIS ALL cohort (N=10,162), including relapse estimates adjusted for sensitivity. Relapses and HSCTs were higher in infants and in children receiving daunorubicin. We present novel approaches to identify relapse and HSCT events using administrative data, validated at two children's hospitals. Timing of events are matched within ±14 days. Relapse estimates are slightly lower than clinical trial data, but this approach has higher sensitivity than published administrative data reports, and sensitivity-adjusted rates approximate clinical trial data. Detected events are likely to be true based on the 100% PPV. Our relapse identification approach is complex and requires disease-specific clinical expertise to identify relapse-style chemotherapy patterns in children on therapy; however, this approach can capture early relapses in children outside of clinical trials. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding.
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Kliman, David Simon, Louise Imlay-Gillespie, Kirsten McIlroy, Anthony Gill, Christopher Arthur, Luke Coyle, Keith Fay, et al. "Risk Stratification Combining MYC Immunohistochemistry with Standard IPI Has Utility in Patients with Diffuse Large B-Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 2656. http://dx.doi.org/10.1182/blood.v126.23.2656.2656.
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Abstract Background Though the majority of patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) are curable with R-CHOP chemotherapy, a significant proportion will relapse or have refractory disease. The most commonly used clinical tool is the international prognostic index (IPI), though this cannot fully capture the heterogeneity of cases seen in practice. In recent years biomarkers such as MYC are entering clinical use. Pts with lymphomas demonstrating dual abnormalities of MYC in association with BCL2 and/or BCL6-known as 'double-hit' lymphomas are consistently shown to have poorer disease free and overall survival. While Fluorescence in-situ hybridization (FISH) for MYC translocation is the gold-standard, immunohistochemistry (IHC) is faster and significantly cheaper. Studies in recent years have confirmed the prognostic significance of increased MYC expression by IHC. Due to significant inter-laboratory variability however, internal validation is required. Methods Tissue samples of pts treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012 were retrospectively assessed. Pts were included if they were transplant eligible (age <70 years), and had been treated for de novo DLBCL with a rituximab containing regimen. Samples were scored for MYC IHC as well as BCL2 and BCL6. Clinical data including IPI score, treatment and outcomes were also collected. Treatments were stratified into standard R-CHOP-like versus more intensive regimens including R-Hyper-CVAD and dose-adjusted R-EPOCH. A significant cut-off for MYC staining was determined using X-Tile (Rimmlab, New Haven, CT) and confirmed with the log-rank test. Estimation of OS and EFS was performed using the Kaplan-Meier method. Pt characteristics were compared using Chi-squared test. Statistical analysis was performed using MedCalc 15.4 (MedCalc software, Ostend, Belgium). Ethics approval was received for a retrospective study. Results 105 patients met study criteria. The 5 year OS and EFS was 86% and 77% respectively (Figure 1 and 2). The optimal cut-off for positive MYC IHC was >70%. This was seen in 23% of samples. From the 13 cases with MYC FISH results, the positive and negative predictive values of positive MYC IHC were 50% and 92% respectively. There was no significant difference between the MYC positive and negative groups with respect to demographics or IPI score (Table 1). Significantly more patients with MYC positivity received intensive treatment (37% versus 16%, p=0.047). Despite this, 5 year OS was significantly poorer at 51% versus 87% at median follow-up of 40 months (P=0.0025, Figure 3). There was a trend towards worse EFS at 61% versus 75% though this did not reach statistical significance (P=0.242). On multivariate analysis, MYC IHC and IPI score were the only independent prognostic factors. Based on the relative odds ratio, a combined scoring system was designed, attributing 1 point for positive MYC IHC and/ or IPI intermediate-high risk, and 2 points for IPI high risk. This resulted in 4 risk groups with significantly different 5 year OS of 94%, 78%, 45% and 0% (P<0.0001). Discussion MYC IHC is of independent prognostic significance. Due to significant variability between laboratories, local validation is required. A composite score combining IPI and MYC IHC is simple to calculate and may provide better prognostic utility than either factor alone. Ongoing prospective studies investigating the role of clinical risk stratification and newer biomarkers are required to identify patients likely to need more intensive or novel therapies. Figure 1. Figure 1. Disclosures Imlay-Gillespie: Novartis: Honoraria. Arthur:Amgen: Honoraria; Novartis: Honoraria; BMS: Honoraria. Mackinlay:Roche: Research Funding; Sanofi Aventis: Research Funding. Mulligan:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding.
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Putri, Meyrna Heryaning, Pudji Rahaju, and Dyah Indrasworo. "Hubungan ototoksisitas dan kemoterapi neoadjuvan pada karsinoma nasofaring berdasarkan ASHA, CTCAE, dan DPOAE." Oto Rhino Laryngologica Indonesiana 47, no. 2 (January 7, 2018): 102. http://dx.doi.org/10.32637/orli.v47i2.219.
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Latar belakang: Kemoterapi neoadjuvan adalah induksi kemoterapi sebelum radioterapi dengan regimen cisplatin dan 5-Fluorouracil. Kemoterapi cisplatin bersifat ototoksik pada pendengaran sensorineural bilateral progresif dan bersifat irreversible. Kriteria dari American Speech-Language Hearing Association (ASHA) dan Common Terminology Criteria for Adverse Events (CTCAE) merupakan kriteria untuk mengidentifikasi ototoksisitas dengan menggunakan audiometri, selain pemeriksaan Distortion Product Otoacoustic Emissions (DPOAE). Tujuan: Mengidentifikasi hubungan ototoksisitas dengan kemoterapi neoadjuvan pada penderita karsinoma nasofaring (KNF) WHO tipe III menggunakan ASHA, CTCAE, serta DPOAE. Metode: Studi ini adalah penelitian observasional dengan desain cohort. Kriteria inklusi penelitian yaitu penderita baru KNF WHO tipe III, yang mendapatkan kemoterapi regimen standar dan berusia <60 tahun. Kriteria pemeriksaan DPOAE adalah penderita dengan ambang dengar ≤40 dB. Percontoh dilakukan pemeriksaan timpanometri, audiometri, dan DPOAE. Hasil: Terdapat 9 sampel percontoh penelitian. Uji repeated-ANOVA menunjukkan tidak ditemukan perbedaan bermakna pada tiga hasil pengukuran audiometri antara pascakemoterapi pertama, kedua, dan ketiga (p>0,05). Deteksi awal ototoksisitas menggunakan kriteria ASHA menunjukkan sensitivitas sebesar 67% dan dan CTCAE 44%, dibandingkan baku emas menggunakan DPOAE. Kesimpulan: Ototoksisitas cisplatin ditemukan sejak kemoterapi pertama dengan menggunakan pemeriksaan DPOAE walaupun tidak bermakna secara statistik. Kemampuan DPOAE untuk mendeteksi awal ototoksisitas lebih baik dibandingkan kriteria ASHA dan CTCAE yang menggunakan audiometri nada murni.Kata kunci: Karsinoma nasofaring, ototoksisitas sisplatin, DPOAE, CTCAE, ASHA ABSTRACT Introduction: Neoadjuvant chemotherapy is induction chemotherapy before radiotherapy with cisplatin and 5-Fluorouracyl regiment. Chemotherapy cisplatin is ototoxic, leads to frequently progresive and irreversible bilateral sensorineural hearing loss. American Speech-Language Hearing Association (ASHA) and Common Terminology Criteria for Adverse Events (CTCAE) are the criteria to determine ototoxicity with audiometry, beside Distortion Product Otoacoustic Emissions (DPOAE). Purpose: To identify the relationship between ototoxicity with neoadjuvant chemotherapy in patients NPC WHO type III using ASHA, CTCAE, and DPOAE. Method: This observational study approach with cohort design. Inclusion criteria: new patients NPC WHO type III who consented to undergo standard regiment chemotherapy, and age <60 year-old. For DPOAE examination: hearing level ≤40 dB. Exclucion criteria: NPC WHO type III patients who underwent chemotherapy with unconventional standard regiment. Examinations for hearing function conducted with tympanometry, pure tone audiometry, and Distortion Product Otoacoustic Emissions (DPOAE). Result: There were 9 sample in this study. The result of Repeated-ANOVA test showed no significant difference in three audiometry measurements among three series of chemotherapies. Early detection of ototoxicity using ASHA and CTCAE criterias showed sensitivity of 67% and 44% (compared with DPOAE as a gold standard). Conclusion: Cisplatin ototoxicity had occured since the first chemotherapy and detected with DPOAE, but statistically was not significantly related. Early detection of cisplatin ototoxicity with DPOAE was much better than with criteria American Speech-Language Hearing Association (ASHA) and Common Terminology Criteria for Adverse Events (CTCAE), which used pure tone audiometry.Keywords: Nasopharyngeal carcinoma, cisplatin ototoxicity, DPOAE, CTCAE, ASHA
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Park, Hanahlyn M., Vicky Sandhu, Paul Fearn, Kathleen Shannon Dorcy, Elihu H. Estey, and Emily Silgard. "Using Natural Language Processing to Determine Chemotherapeutic Regimens Administered within 30 Days Prior to Death in Acute Myelogenous Leukemia Patients." Blood 124, no. 21 (December 6, 2014): 1267. http://dx.doi.org/10.1182/blood.v124.21.1267.1267.
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Abstract Background Clinical research in AML relies heavily on databases. Typically patients’ medical records are examined manually with relevant data entered into the database. This process is slow and subject to human error. Natural Language Processing (NLP) is a technique used to build and train computer algorithms to automatically extract structured data elements from unstructured text. Although, we have not used NLP extensively, the potential exists to use NLP as a tool to ease the time and resource-intensive burden of manual data abstraction. Since many of the data elements needed for clinical and translational research, quality metrics, and operations and analytics, are the same throughout FHCRC/UW/SCCA, the biomedical informatics group at FHCRC has decided to invest in the creation of an enterprise wide NLP pipeline to improve the efficiency and quality of data extraction for researchers, clinicians, and administrators throughout FHCRC/UW/SCCA. Purpose For this pilot project, an NLP system was trained and tested against a manually curated dataset to determine whether chemotherapeutic regimens were administered within 30 days prior to death in AML patients. The first part of this project was to train the NLP system with a small sample of patients in order to build in rules and logic about how to find both a patient’s date of death and the evidence of a completed chemotherapeutic agent. The second phase was to test the algorithm with unseen data from another set of patients and determine the system’s overall performance in finding the patient’s date of death and determining if they received chemotherapy within the preceding 30 days. Methods Inclusion criteria were the following: AML patients who came to FHCRC/SCCA/UWMC between 1/1/2010 to 12/31/2012, whose age ≥ 18 years, and who received chemotherapeutic agents within 30 days of death. Total sample size was 54 patients. Training sample was 24 patients and testing sample was 30 patients. In order to see the accuracy of the trained NLP system, manual and automatic extraction of data sets were compared. The performance of the system was evaluated in two ways: predicted value of a retrieved NLM identification (the number of correctly retrieved results out of all retrieved results) and sensitivity (the number of correctly retrieved results out of all possible correct results in the gold standard training and testing data). These two metrics will help determine if NLP can be a useful data extraction aid in order to expedite real time access to data analysis for improvement in outcomes for AML patients. Results For the training sample, the predictive value of a retrieved result by NLM of finding both the date of death and chemotherapeutic agents was 100%. The sensitivity of both date of death and chemotherapeutic agents was 92% in training sample. For the testing sample, the predicted value of a NLM identification was for finding date of death and chemotherapeutic agents was 96% while sensitivity of both date of death and chemotherapeutic agents was 73%. Limitations Sensitivity, in both training and testing populations, is primarily affected because of the ubiquitous problem of not having a concrete record of many patients’ death. Often patients go back to local facilities for continuing care and are lost to follow-up. The precision of finding date of death in the testing sample was affected by one date of death that was pulled incorrectly from a clinic note due to an error in the NLP algorithm. The recall of finding chemotherapeutic agents in the testing sample was affected by the lack of recognition of a chemotherapeutic trial name that had not appeared in the training sample. Conclusion The results of this pilot give us a preliminary idea of the feasibility of the NLP algorithm to perform in the future. Although the trained NLP tool only recalled 70-80% of the two data elements (date of death, chemotherapeutic agents), this was primarily due to the absence of certain data elements in the electronic health record and the precision of the defined date elements was nearly perfect. With the given results, we conclude that NLP can be a useful tool for data extraction purposes which will potentially maximize the ability of the leukemia service to have earlier access to data relative to symptom management and disease response which will influence the development of new clinical pathways for the optimizing of care and possible improvement in outcomes for AML patients. Disclosures No relevant conflicts of interest to declare.
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Leclerc, Mathieu, Régis Peffault de Latour, Mauricette Michallet, Didier Blaise, Patrice Chevallier, Pierre-Simon Rohrlich, Pascal Turlure, et al. "Reduced Intensity Versus Myelo-Ablative Conditioning Regimen before Allogeneic Hematopoietic Stem Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A Retrospective Study of the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)." Blood 126, no. 23 (December 3, 2015): 3208. http://dx.doi.org/10.1182/blood.v126.23.3208.3208.
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Abstract Introduction Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare form of acute leukemia associated with an overall bad prognosis. Only very few cases have been reported to reach durable remissions thanks to chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) using a myelo-ablative conditioning regimen (MAC) has been reported to be the gold standard treatment for BPDCN (Roos-Weil et al, 2013). However, little is known about the place of reduced-intensity/non-myelo-ablative conditioning regimens (RIC/NMA) in this setting. Methods We retrospectively collected from the database of the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) all cases of BPDCN treated with allogeneic HSCT. Immunophenotypes at diagnosis were centrally reviewed in order to confirm diagnosis according to the Garnache-Ottou diagnostic criteria (Garnache-Ottou et al, 2009). Twenty-eight patients had a diagnostic score of 2 or more. The remaining 15 patients all had CD4+ CD56+ disease, but as they were mostly diagnosed before publication of this score, other markers (such as CD123, BDCA-2 and BDCA-4) were not performed routinely at that time, precluding calculation of a score at least equal to 2. Results From February 2003 to January 2014, 43 patients with BPDCN received an allogeneic HSCT in 21 French centers. PatientsÕ characteristics are summarized in table 1. Median age was 57 (range: 20-72), sex ratio (M/F) was 2.1/1 and most patients were in CR1 at time of transplant. Sibling transplantation was performed in 42% of cases. Peripheral blood was the main source of stem cell used in this study (70% of cases). Conditioning regimens were MAC in 18 cases (42%) and RIC/NMA in 25 cases (58%, table 2). Four patients (9%) had engraftment failure or secondary graft rejection, 3 of whom having received cord blood units. All these 4 patients were transplanted again 2 to 17 weeks after the first transplant. After a mean follow-up of 668 days for the entire cohort (1050 days for alive patients), 22 patients (51.2%) were alive, 19 of whom being disease-free (44.2%). Eleven patients had relapsed, at a median of 225 days post-HSCT (range: 74-821 days). Two-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 25.5% (95% CI = [0.13-0.40]) and 32.8% (95% CI = [0.186-0.479]) respectively (figure 1). At 2 years post-transplant, disease-free survival (DFS) and overall survival (OS) were 44.9% (95% CI = [0.291-0.595]) and 52.2% (95% CI = [0.357-0.664]), respectively. Even though not statistically significant, patients receiving a MAC (n = 18) were less likely to relapse than patients receiving RIC/NMA (2-year CIR = 7.1% and 36% respectively, P = 0.137), but had a higher NRM rate (43.9% versus 26% at 2 years, P = 0.419), resulting in similar 2-year DFS and OS (57.1% versus 38%, P = 0.511 and 57.1% versus 49.7%, P = 0.91). There was a trend for a lower incidence of NRM at 2 years in patients transplanted from a sibling donor versus others (16.7% and 39.9% respectively, P = 0.0505, figure 2), but donor source had no effect on CIR (P = 0.826), DFS (P = 0.194) and OS (P = 0.188). Conclusion In this series of 43 patients with BPDCN, allogeneic HSCT was associated with a good disease control, but NRM was high. In this regard, transplantation from a sibling donor appears to be the best option. RIC/NMA are feasible and may also reduce the incidence of NRM, but at the expense of a higher incidence of relapse. Table 1. Patients' characteristics N 43 Age 57 (20-72) Sex (M/F) 29/14 Time from diagnosis (days) 170 (107-1050) Disease status at HSCT CR1 34 (79%) CR2 5 (12%) No CR 2 (5%) Unknown 2 (5%) Donor Sibling 18 (42%) Unrelated 23 (53%) Mismatch relative 2 (5%) Cell source Bone Marrow 7 (16%) Peripheral Blood 30 (70%) Cord Blood 6 (14%) Conditioning regimen MAC 18 (42%) RIC/NMA 25 (58%) CMV status (D/R) -/- 18 (42%) -/+ 9 (21%) +/- 4 (9%) +/+ 12 (28%) GVHD prophylaxis Ciclo/MTX 15 (35%) Ciclo/MMF 19 (44%) Ciclo alone 5 (12%) Other 2 (5%) Unknown 2 (5%) Table 2. Conditioning regimens MAC 14 Cy/TBI 11 Cy/TBI 12 Gy 9 Cy/TBI 10 Gy 1 Cy/Flu/TBI 12 Gy 1 Bu/Cy 3 RIC/NMA 29 Flu/Bu/ALG 10 Flu/TBI 2 Gy 10 Flu/TBI 2 Gy 5 Cy/Flu/TBI 2 Gy 4 AraC/Flu/TBI 2 Gy 1 Sequential 5 Amsa/AraC/Flu/Cy/Bu/ALG 3 Amsa/AraC/Flu/Cy/TBI 2 Gy/ALG 1 Amsa/AraC/Flu/Bu/ALG 1 Flu/Bu/Thiotepa/ALG 1 Flu/Mel 1 Cy/TBI 8 Gy 1 TLI/ALG 1 Figure 1. Cumulative incidences of relapse and non-relapse mortality Figure 1. Cumulative incidences of relapse and non-relapse mortality Figure 2. Non-relapse mortality according to donor type Figure 2. Non-relapse mortality according to donor type Disclosures No relevant conflicts of interest to declare.
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Rossi, Adriana C., Tomer M. Mark, Kevin Wood, Roger N. Pearse, Faiza Zafar, Karen Pekle, Stanley Goldsmith, and Ruben Niesvizky. "PET/CT Evaluation As a Prognostic Indicator In Relapsed Or Refractory Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 1878. http://dx.doi.org/10.1182/blood.v122.21.1878.1878.
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Abstract Background Conventional radiography remains the gold standard imaging modality for staging multiple myeloma (MM). Other imaging modalities have been evaluated in recent years, and been shown to provide additional information about disease burden and location. FDG-PET/CT has proven to be useful in the identification of extramedullary disease and in monitoring patients with non-secretory myeloma. In addition to diagnostic utility, FDG-PET/CT has also been shown to predict time to relapse in the setting of newly diagnosed MM. However, to our knowledge its utility as a prognostic indicator in relapsed or refractory disease has not been studied. Methods We conducted a retrospective analysis of 61 patients with relapsed or refractory multiple myeloma (RRMM) who underwent PET/CT imaging prior to receiving salvage chemotherapy on a therapeutic trial of ClaPD (clarithromycin, pomalidomide, dexamethasone). Patients were heavily pre-treated, having received a minimum of 3 prior lines of therapy (range 3-15). All imaging was performed on the same PET/CT system at a single institution. Each PET/CT was evaluated in blinded fashion by two independent nuclear medicine physicians, with attention to the number and type of lesion, maximum SUV, and presence or absence of extramedullary disease. Disease response evaluation was performed monthly, and measured according to the international uniform response criteria. Multivariate analysis was performed to assess relationships of the above variables to depth of response, progression free survival (PFS), and overall survival (OS). Results Of 61 evaluable patients, 23 (38%) had no lytic lesions, 12 (20%) had <5 lytic lesions, and 26 (42%) had >5 lytic lesions on FDG-PET/CT. It is worth noting that 10 patients (16%) were found to have extramedullary disease, 8 of whom had >5 lytic bone lesions. There was no correlation between FDG-PET/CT findings and depth of response or median PFS, however patients with >5 lytic lesions had a median OS of 5.8 months, while it has not yet been reached for the other groups. At a median follow up of 13.2 months, 17 patients (74%) with no lytic lesions and 7 (58%) of those with <5 lytic lesions are alive. Conclusions The presence of >5 lesions on PET/CT at time of relapse is associated with poor prognosis in our cohort of heavily pre-treated patients with relapsed or refractory multiple myeloma receiving salvage chemotherapy with ClaPD. The presence of extramedullary disease, seen mostly in patients with >5 lesions, may contribute to our findings. Further studies in patients with relapsed or refractory MM are needed to evaluate the prognostic utility of FDG-PET/CT in this setting, as well as to extend these findings to other salvage regimens. Disclosures: Rossi: Celgene: Speakers Bureau. Mark:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Calò, Beppe, Michele Marchionni, Francesca Sangusedolce, Ugo Giovanni Falagario, Marco Chirico, Giuseppe Carrieri, and Luigi Cormio. "Neoadjuvant Chemotherapy Before Radical Cystectomy: Why We Must Adhere?" Current Drug Targets 22, no. 1 (December 31, 2020): 14–21. http://dx.doi.org/10.2174/1389450121666200802022150.
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Aim: To provide a critical literature review on state of the art and novel strategies in the field of neoadjuvant treatments for muscle-invasive bladder cancer (MIBC). Methods: a nonsystematic literature review was performed using PubMed, Scopus and Clinical Trials.gov to retrieve papers related to neoadjuvant treatments for MIBC over the past 15 years. Prospective and retrospective studies were included. Results: Platinum-based treatment is the gold standard and mainly consists of a combination of Cisplatin with Vinblastine, Methotrexate, Doxorubicin, Gemcitabine, Adriamycin or even Epirubicin. The 5-year absolute overall survival benefit of MVAC is 5% and the absolute disease-free survival improves by 9%. CMV treatment is associated with a 10-year overall survival improving from 30% to 36% and a 16% reduction in mortality. Gemcitabine and cisplatin regimen provides complete response in 20% of cases, with non-inferior oncological outcomes compared to MVAC regimen. Recent prospective trials investigating neoadjuvant immunotherapy show high rate of complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. The tyrosine kinase inhibitor pathway is being explored and could offer an interesting strategy to improve survival outcomes. Conclusions: Available evidence suggest better oncological outcomes for MIBC patients receiving neoadjuvant treatment before radical cystectomy. While MVAC remains the standard of care in cisplatin eligible patients, novel strategies are under development for cisplatin ineligible patients whereby immunotherapy seems to hold great promise.
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Orgel, Etan, Nicole Mueske, David Robert Freyer, and Steven D. Mittelman. "Correlation of Body Mass Index to Dual-Energy X-Ray Absorptiometry in Assessment of Body Composition during Therapy for Childhood Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 3663. http://dx.doi.org/10.1182/blood.v124.21.3663.3663.
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Abstract Introduction Obesity is associated with increased morbidity and mortality in children diagnosed with high-risk acute lymphoblastic leukemia (HR-ALL). The mechanism of this adverse influence is thought to be due to adipose tissue and adipokines affecting immune function and/or decreasing chemotherapy efficacy. Adiposity, and not body weight, is therefore the central feature for exploring the influence of obesity on outcome in HR-ALL. To date, multiple international consortia have investigated this association using the surrogate measure of Body Mass Index (BMI). BMI estimates body composition based on height and weight and is therefore not able to distinguish between fat mass, bone density, and lean muscle. While BMI is generally a good indicator of overall adiposity, changes in weight that may occur over the course of therapy reflect not only a change in fat mass, but also changes in other components of body composition. We therefore hypothesized that BMI may not be a sensitive measure for assessing change in adiposity during therapy. Methods Body composition was assessed serially by BMI and the gold-standard Dual-energy X-ray Absorptiometry (DXA) as an ancillary aim in children with newly diagnosed HR-ALL enrolled on a prospective clinical trial investigating bone health. Children were treated as per Children’s Oncology Group HR-ALL regimens (CCG1961, AALL0232, AALL1131). Body composition was compared at three time-points (TP): within 24 hours of diagnosis (TP1), 28 days later (TP2, end of induction), and at the end of delayed intensification (TP3, mean interval of 8.2 months in the cohort). Age and tanner stage at diagnosis, gender, and ethnicity were collected. DXA was used to analyze body composition as defined by total mass of “body minus head” and separated into respective percentages of lean muscle, fat mass, and bone mineral content. BMI was converted to a percentage per Center for Disease Control and Prevention age- and gender- population norms. BMI percentage was compared to body fat percentage (BF%) overall and individually at each TP. Changes in body composition across TPs were evaluated by DXA. IRB approval was obtained and informed consent documented for all subjects. Results Of 51 subjects enrolled in the trial, a sub-cohort of 34 (66.6%) had sufficient DXA data for analysis. Of these, 85% (29/34) had DXA and BMI data at all 3 TPs, while 5/34 were too ill at diagnosis to complete the imaging. There were no significant differences in age, gender, and tanner stage between those included in the DXA sub-cohort and excluded; the cohort with DXA data consisted of a significantly higher prevalence of self-identified Hispanic subjects (31/34, 91% vs 11/17 65%). BF% by DXA was significantly correlated with BMI when observations from all TPs were combined (n=96, Spearman rho 0.6, p=0.002) and at each TP (TP1 rho=0.6, p=0.002; TP2 rho =0.7, p<0.001;TP3 rho=0.6, p=0.002). When change in BMI was compared to change in BF%, however, there was no significant correlation (TP1 vs TP2 rho=0.3, p=0.189; TP1 vs TP3 rho=0.1, p=0.632). Change in weight also did not correlate with change in BF% (TP1 vs TP2 rho=-0.2, p=0.420; TP1 vs TP3 rho=0.2, p=0.311); in fact, average BF% increased across all TPs despite a decrease or no change in weight (Table 1). On evaluation by DXA, change in weight was noted to be primarily due to a loss in lean muscle and gain in fat mass (Table 1). Conclusion BMI is an adequate cross-sectional assessment of obesity but was insufficient to assess longitudinal changes in body composition. Continued investigation into the association between ALL and obesity would be aided by prospective trials utilizing the gold-standard DXA or similarly sensitive measurements. Table 1 Variable At Diagnosis End of Induction (+28 days) End of Delayed Intensification (+8 months) Median, Mean (SD) Range Median, Mean (SD) Range Median, Mean (SD) Range BMI percentile 88.1, 72.4 ( 31.6) 0.2 – 99 77.7, 63.2 (33.4) 0 - 99.2 73, 62.4 (34.6) 0.2 - 99.6 Weight (Kg) 59.4, 61.6 (20.0) 23.7 – 105.5 59.4, 58.0 (18.7) 24.1 - 105 58.5, 60.1 (20.4) 25.0 – 110.6 Percent Body Fat 27.8, 28.3 (9.1) 8.7 – 45.8 33.6, 35.3 (10.3) 14.2 – 63.7 39.3, 38.5 (8.3) 20.0 – 52.1 Percent Lean Muscle 69.3, 68.9 (8.8) 52.2 – 87.3 63.4, 61.8 (10.0) 34.3 – 81.8 57.5, 58.7 (7.9) 45.4 – 76.1 Percent Bone Mineral Content 2.8, 2.8 (0.5) 1.7 – 4.0 2.9, 3.0 (0.6) 1.9 – 4.0 2.6, 2.6 (0.6) 1.7 – 3.9 Disclosures No relevant conflicts of interest to declare.
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Shi, Qian, Norbert Schmitz, Christopher Flowers, Fang-Shu Ou, David Cunningham, Michael Pfreundschuh, John F. Seymour, et al. "Evaluation of Progression-Free Survival (PFS) As a Surrogate Endpoint for Overall Survival (OS) in First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Findings from the Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 7507 Patients." Blood 128, no. 22 (December 2, 2016): 4196. http://dx.doi.org/10.1182/blood.v128.22.4196.4196.
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Abstract Background OSis the gold standard primary efficacy endpoint for evaluating treatment strategies for DLBCL. Because current standard of care first-line regimens with rituximab plus chemotherapy produce median OS > 8 years, an endpoint assessed earlier would accelerate the evaluation of new therapies and potentially allow patients (pts) to more rapidly benefit from study results. The SEAL group formally evaluated PFS as a surrogate endpoint for OS in first-line therapy for DLBCL. Methods Through a systematic literature search and input from lymphoma experts on the SEAL committee, we identified multicenter, randomized controlled clinical trials that evaluated active treatment and enrolled at least 100 pts with previously untreated DLBCL or aggressive non Hodgkin lymphoma by WHO/REAL classification, published after January 1, 1995. Studies which enrolled only early stage (I or II) pts and studies that could not provide individual pt data (IPD) were excluded from surrogacy analysis. Potential surrogate candidates for OS included: 1) PFS, defined as the time from initiation of induction treatment to progressive disease, relapse or death due to any cause, and 2) PFS rate at 24 months after initiation of induction treatment (PFS24). These endpoints were derived consistently for all studies based on IPD. Surrogacy was evaluated by the correlation between surrogate candidates and OS. Pt-level correlation was measured by the rank correlation coefficient (ρ) and global odds ratio for PFS and PFS24, respectively, estimated by the Copula model. Trial-level correlation was evaluated by the correlation between trial-specific treatment effects on surrogate candidates and OS with two commonly used trial-level R2s: R2WLS (Sargent et al JCO 2005) and R2Copula (Burzykowski et al J R Stat Soc C 2001 and Burzykowski et al J R Stat Soc A 2004). For the R2 measures, a value closer to 1 indicates a stronger correlation. We pre-specified that if either trial-level R2 was >=0.80 and its 95% confidence interval (CI) excluded 0.60, the candidate would meet criteria for surrogacy. Results Thirteen of 14 studies collected to date in the SEAL database met all inclusion criteria. IPD for 7507 pts (median age 63 years, 54% male, 46% ECOG performance status 0, 8% IPI 0, 50% IPI 1-2, 64% stage III/IV, median follow-up time of 52 months) were analyzed. Among 13 studies, one tested maintenance treatment only and two tested both induction and maintenance regimens. One study included four treatment arms. Thus at the trial level, 17 two-arm comparisons were formed: 14 comparisons comparing induction regimens and 3 comparing maintenance; 15 comparisons involved rituximab. Longer PFS was highly correlated with longer OS at the pt level (ρ= 0.85, 95% CI 0.84-0.86), as was PFS24 (Global odds ratio = 61.1, 95% CI 52.6-69.6). The Table shows trial-level correlations, and the Figure shows trial-level association between estimated treatment effects (log(HR) [hazard ratio]) on PFS and OS. The trial-level correlation between PFS and OS was strong and met the pre-specified surrogacy criteria, with R2WLS of 0.83 (95% CI 0.58-0.94) and R2Copula of 0.85 (95% CI 0.72-0.99). Sensitivity analyses including only comparisons including rituximab or only induction regimens showed consistent results. The overall trial-level correlation between PFS24 and OS was reduced slightly, with R2WLS of 0.77 (95% CI 0.49-0.92) and R2Copula of 0.78 (95% CI 0.59-0.96). Performance of PFS24 was improved when restricting analysis to only including induction studies (see table). Conclusion This large IPD pooled-analysis demonstrates that PFS duration met the pre-specified criteria as a robust surrogate endpoint for OS, and can be considered as a surrogate endpoint for OS for frontline DLBCL trials evaluating immunochemotherapy. The earlier endpoint of PFS24 showed promise as a potential surrogate and further validation is warranted. Figure Figure. Disclosures Shi: Mayo Clinic: Employment. Flowers:Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Consultancy, Research Funding; NIH: Research Funding; Mayo Clinic: Research Funding; ECOG: Research Funding; Acerta: Research Funding; Infinity: Research Funding; AbbVie: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ou:Mayo Clinic: Employment. Cunningham:Merrimack: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Astra-Zeneca: Research Funding; Amgen: Research Funding; Medimmune: Research Funding. Pfreundschuh:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Haioun:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Herbrecht:Cell Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Flament:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Coiffier:MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sargent:Celgene: Research Funding.
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Motoi, Fuyuhiko, and Michiaki Unno. "Adjuvant and neoadjuvant treatment for pancreatic adenocarcinoma." Japanese Journal of Clinical Oncology 50, no. 5 (February 21, 2020): 483–89. http://dx.doi.org/10.1093/jjco/hyaa018.
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Abstract The prognosis of pancreatic adenocarcinoma is dismal. Hence, advances in multidisciplinary treatment strategies, including surgery, are urgently needed. Early recurrence of distant organ metastases suggests that there are occult metastases even in cases with resectable disease. Several randomized controlled trials on adjuvant chemotherapy have been conducted to prolong survival after resection. CONKO-001 study was the first to demonstrate significant improvement in disease-free survival after surgery with gemcitabine administration. The JASPAC-01 study showed the superiority of adjuvant S1 over gemcitabine in survival after resection. Based on the results, adjuvant S1 therapy is the prescribed standard of care in Japan. Recently, the PRODIGE 24/CCTG PA.6 study showed that survival of patients treated with a modified FOLFIRINOX regimen as adjuvant therapy was significantly longer than those treated with adjuvant gemcitabine therapy. Although the evidence from these trials on adjuvant chemotherapy have been the gold-standard treatment for curatively resected and fully recovered patients, resectable disease at diagnosis is not the status, resected disease after curative resection. Currently, neoadjuvant therapy is considered to be a promising alternative to surgery for pancreatic cancer. Although there are many reports regarding neoadjuvant chemoradiotherapy, so far there has been no solid evidence proving the advantage of this strategy versus standard up-front surgery. Newly obtained results from the Prep-02/JSAP05 randomized phase II/III study, comparing neoadjuvant therapy with up-front surgery, revealed significant improvement in overall survival with neoadjuvant chemotherapy by intention-to-treat analysis. Thus, neoadjuvant intervention might become a new standard strategy in cases undergoing planned resection for pancreatic cancer.
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Darlix, Amélie, Emmanuel Mandonnet, Christian F. Freyschlag, Daniel Pinggera, Marie-Therese Forster, Martin Voss, Joachim Steinbach, et al. "Chemotherapy and diffuse low-grade gliomas: a survey within the European Low-Grade Glioma Network." Neuro-Oncology Practice 6, no. 4 (December 13, 2018): 264–73. http://dx.doi.org/10.1093/nop/npy051.
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Abstract Background Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.