The efficacy and safety of gemcitabine-based induction chemotherapy for locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiation: A meta-analysis.

OBJECTIVES: To assess the efficacy and toxicity of gemcitabine-based induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Both observational studies (OBS) and randomized controlled trials (RCT) were included in the meta-analysis. Systematic online searches were conducted in Web of Sciences, PubMed, Embase, meeting proceedings and ClinicalTrials.gov from the inception to May 25, 2020. The primary endpoint of interest was overall survival. RESULTS: five OBSs and 2 RCTs including 1680 patients were incorporated in the analysis. The evidence from the RCTs showed that adding gemcitabine-based induction chemotherapy to CCRT significantly improved progression free survival (hazard ratio (HR): 0.60, 95% confidence interval (CI): 0.40-0.88; P = .010; chi square P = .25; I2 = 24%) and overall survival (HR: 0.47; 95% CI: 0.28-0.80; P = 0.005; chi square P = .49, I2 = 0%) and was related to a higher risk of hematological toxicities. Furthermore, based on the data of OBSs, overall survival (HR: 0.52; 95% CI: 0.31-0.88; P = .02; chi square P = .37, I2 = 6%) was significantly improved in patients treated with gemcitabine-based induction chemotherapy compared to those treated with taxane-based induction chemotherapy. However, the progression free survival (HR: 0.67; 95% CI: 0.45-1.01; P = .06; chi square P = .74; I2 = 0%) showed no significant difference. CONCLUSIONS: For LA-NPC patients, adding gemcitabine-based induction chemotherapy to CCRT significantly improved overall survival and progression free survival with a higher risk of hematological toxicities when compared to CCRT alone. Also, gemcitabine-based regimen could be used as an alternative induction chemotherapy regimen to taxane-based regimen in the treatment of LA-NPC.

The efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

BACKGROUND: A systemic review and meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy, toxicity and safety of concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) for locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Research searching was performed in Web of Science, PubMed, The Cochrane Library, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chongqing VIP Database for Chinese Technical Periodicals and Wanfang Database. RCTs including patients diagnosed with locoregionally advanced NPC without metastasis and randomly treated with IC plus CCRT and CCRT alone were included. Survival and outcome data were extracted and meta-analysis was performed using the Revman 5.3.0 software. RESULTS: Ten RCTs (2280 patients) were selected and used for pooled meta-analysis. In comparison with CCRT, IC plus CCRT treatment significantly improved the overall survival (OS; HR = 0.70, 95%CI 0.56-0.87, P = .002), progression-free survival (PFS; HR = 0.75, 95%CI 0.65-0.87, P < .0001), distant metastasis failure-free survival (DMFS; HR = 0.71, 95%CI 0.58-0.85, P = .0003) and loco-regional failure-free survival (LFES; HR = 0.72, 95%CI 0.59-0.88, P = .002) of patients with locoregionally advanced NPC. Patients treated with IC and CCRT had higher incidence of grade 3-4 leucopenia and thrombocytopenia than patients treated with CCRT alone (P < .0001). No significant difference in other grade 3-4 adverse events and radiation toxicity was observed between the two groups. IC combined with CCRT improved the survival of patients with locoregionally advanced NPC. CONCLUSIONS: Combined IC and CCRT therapy was an efficacy treatment regimen for locoregionally advanced NPC.

Emerging agents and regimens for treatment of relapsed and refractory acute myeloid leukemia.

Relapsed and refractory acute myeloid leukemia (R/R AML) has complicated pathogenesis. Its treatment is complicated, and the prognosis is poor. So far, there is no consensus on what is the optimal treatment strategy. With the deepening of research, new chemotherapy regimens, new small molecule inhibitors, and immunotherapy have been increasingly applied to clinical trials, providing more possibilities for the treatment of R/R AML. The most effective treatment for patients who achieve complete remission after recurrence is still sequential conditioning therapy followed by allogeneic hematopoietic cell transplantation. Finding the best combination of treatments is still an important goal for the future.

Induction therapy with thymoglobulin or interleukin-2 receptor antagonist for Chinese recipients of living donor renal transplantation: a retrospective study.

BACKGROUND: Recipients of living donor renal transplantation are typically considered to have a relatively lower immunological risk. This retrospective study aimed to compare the therapeutic efficacy and safety between rabbit antithymocyte globulin (rATG) or interleukin-2 receptor antagonist (IL2-RA) induction therapies in Chinese population. METHODS: A total of 188 patients receiving living donor renal transplantation between February 2004 and December 2013 were included and divided into the rATG group and based on their induction therapy. The primary outcome was clinically-suspected rejection. The incidences of de novo donor-specific antigen (dn-DSA), graft survival, and infection were also compared between groups. A multivariate Cox regression analysis was performed to investigate the influential factors associated with clinically-suspected acute rejection and graft survival. RESULTS: The rATG group had a higher panel reactive antibody (PRA) score and more complete HLA mismatches than the IL2-RA group (both P < 0.001). The incidences of clinically-suspected acute rejection (9.8% vs. 8.8%; P = 0.832) and dn-DSA formation (4.9% vs. 5.4%, P = 0.44) were not significantly different between groups. Kaplan-Meier curve analysis demonstrated that the graft survivals of two groups were comparable (P = 0.857). After adjusting for patients' age, sex, PRA, HLA mismatch confounders, and the use of corticoids, the multivariate Cox regression analysis showed that methods of induction therapy were not associated with clinically-suspected acute rejection and graft survival (both P > 0.05). The incidences of complications (infections, pneumonia, liver injury and myelosuppression) were all comparable between groups (all P > 0.05). CONCLUSIONS: These results suggested that rATG could be a safe and efficient immunosuppressant when used in a Chinese recipient population with a higher immunological risk in living donor renal transplantation.

Impact of increased access to novel agents on the survival of multiple myeloma patients treated at a single New Zealand centre.

BACKGROUND: The impact of changes in novel agent (NA) usage on the survival of multiple myeloma (MM) patients in real-world hospital settings is unclear. In New Zealand (NZ) in 2011, frontline bortezomib became available and thalidomide availability was expanded. AIM: This retrospective study analyses the impact these change had on the survival of MM patients treated at a NZ hospital. METHODS: Clinical and overall survival (OS) data were collected on MM patients who were treated at Christchurch Hospital during 2000-2009 (pre-cohort, n = 337) and 2011-2017 (post-cohort, n = 343). Outcomes were compared using pre-cohort data truncated at 2011. RESULTS: Patients in the post-cohort had significant increases (P < 0.001) in not only NA usage (85 vs 55%) and OS (median = 56 vs 44 months) but also the proportion (74 vs 49%) of young patients (age < 70) who received an autologous stem cell transplant (ASCT). Separate analysis of older patients demonstrated that those in the post-cohort had significantly longer OS (median OS 28 vs 17, P < 0.001) although 5-year relative survival remained less than 50%. Separate analysis of young patients demonstrated that those in the post-cohort had significantly increased initial OS with the survival curves converging at 5 years. Although ASCT-treated patients had similar OS in each cohort, their progression-free survival (PFS) was significantly increased in the post-cohort (median 40 vs 20 months, P < 0.0001). CONCLUSION: In the setting of a NZ hospital the increased availability of NA was associated with a significant improvement in both the OS of older patients and the PFS of ASCT patients.

From VA Larynx to the future of chemoselection: Defining the role of induction chemotherapy in larynx cancer.

Organ preservation protocols utilizing induction chemotherapy as a selection agent have played a critical role in the treatment of advanced laryngeal squamous cell carcinoma (LSCC). The selection of patients who will have a good response to chemoradiation allows for organ preservation in a significant group of patients and minimizes the rate of surgical salvage. While there remains debate regarding its utility when compared to surgery or other organ preservation regimens, the data does suggest an important role for induction chemotherapy in LSCC. In addition, there are continued opportunities to identify pretreatment biomarkers for induction chemotherapy, whether genetic, epigenetic or cellular, that could predict response to treatment and select patients to therapy (whether organ preservation or surgery). As our understanding of the biology of larynx cancer advances, induction paradigms have utility for the development and adoption of novel agents and therapeutics. The background of induction chemotherapy as a selection agent and future directions of this approach are discussed.

Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

Background: The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens. Design: We nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017. Results: TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further. Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis.

IMPORTANCE: The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. OBJECTIVE: To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. DATA SOURCES: We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: "myeloma" combined with "autologous," "transplant," "myeloablative," or "stem cell." STUDY SELECTION: Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. DATA EXTRACTION AND SYNTHESIS: For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. RESULTS: A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). CONCLUSIONS AND RELEVANCE: The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.

Urine neutrophil gelatinase-associated lipocalin to predict renal response after induction therapy in active lupus nephritis.

BACKGROUND: Tubulointerstitial injury is important to predict the progression of lupus nephritis (LN). Urine neutrophil gelatinase-associated lipocalin (NGAL) has been reported to detect worsening LN disease activity. Thus, urine NGAL may predict renal outcomes among lupus patients. METHODS: We conducted a prospective multi-center study among active LN patients with biopsy-proven. All patients provided urine samples for NGAL measurement by ELISA collected from all patients at baseline and at 6-month follow-up after induction therapy. RESULTS: In all, 68 active LN patients were enrolled (mean age 31.7 ± 10.0 years, median UPCR 4.8 g/g creatinine level with interquartile range (IQR) 2.5 to 6.9 and mean estimated glomerular filtration rate (GFR) 89.6 ± 33.7 mL/min/1.73 m2). At baseline measurement, median urinary NGAL in complete response, partial response and nonresponse groups was 10.86 (IQR; 6.16, 22.4), 19.91 (IQR; 9.05, 41.91) and 65.5 (IQR; 18.3, 103) ng/mL, respectively (p = 0.006). Urinary NGAL (ng/mL) correlated positively with proteinuria and blood pressure, and correlated negatively with serum complement C3 level and estimated GFR. Based on ROC analysis, urinary NGAL (AUC; 0.724, 95%CI 0.491-0.957) outperformed conventional biomarkers (serum creatinine, urine protein, and GFR) in differentiating complete and partial response groups from the nonresponse group. The urine NGAL cut-off value in the ROC curve, 28.08 ng/mL, discriminated nonresponse with 72.7% sensitivity and 68.4% specificity. CONCLUSION: Urine NGAL at baseline performed better than conventional markers in predicting a clinical response to treatment of active LN except serum complement C3 level. It may have the potential to predict poor response after induction therapy.

Enhanced pretreatment CD25 expression on peripheral blood CD4+ T cell predicts shortened survival in acute myeloid leukemia patients receiving induction chemotherapy.

BACKGROUND: Recently, identification of CD25 (interleukin-2 receptor alpha) expression on leukemic blasts was correlated to early treatment failure and unfavorable outcome in acute myeloid leukemia (AML) patients. Here we wished to determine whether quantification of CD25 on peripheral blood CD4+ T cells could improve prognostication in newly diagnosed AML patients. METHODS: The mean fluorescence intensity (MFI) of CD25 expression and frequencies of peripheral blood CD4+ T cells with varying levels of CD25 and CD127 expression were assessed by flow cytometry in all studied individuals. RESULTS: Using univariate (unadjusted) and multivariate (adjusted) analyses we demonstrated that detection of high pretreatment CD25 expression on circulating CD4+ T cells was associated with significantly decreased survival rate of AML patients subjected to standard induction chemotherapy. These associations held true for both entire group of analyzed AML patients and different subgroups of patients identified by presence or absence of favorable and adverse molecular prognostic factors. CONCLUSIONS: Our data indicate that quantification of CD25 expression on peripheral blood CD4+ T cells could become a novel, easily accessible method of shortened survival prognostication of AML patients subjected to standard cytotoxic therapy.

Novel Strategies for Inducing Glycemic Remission during the Honeymoon Phase of Type 2 Diabetes.

A lofty goal in the management of type 2 diabetes is the achievement of glycemic remission. Glycemic remission can be defined as the sustained maintenance of normoglycemia without antidiabetic therapy for variable periods of time after stopping an initial disease-modifying intervention. Although this goal remains largely elusive at this time, growing recognition of the potential reversibility of pancreatic beta-cell dysfunction early in the course of type 2 diabetes has yielded a target for such disease modification. Furthermore, short-term intensive insulin therapy for 2 to 5 weeks has emerged as an intervention that could be applied as a biologic agent for this purpose during a window of opportunity that we have called the honeymoon phase of type 2 diabetes. This recognition has led to a novel therapeutic paradigm consisting of initial induction therapy to improve reversible beta-cell dysfunction during the honeymoon phase, followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. This concept of induction and maintenance therapy is being applied in a series of recent and ongoing clinical trials, toward the goal of ultimately preserving beta-cell function and thereby modifying the natural history of type 2 diabetes.

Impact of failed response to novel agent induction in autologous stem cell transplantation for multiple myeloma.

The aim of this study was to evaluate the impact of the response to induction therapy on the long-term prognosis of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) in the era of novel agents (NAs). A total of 171 patients who were newly diagnosed with MM and underwent early ASCT were analyzed. One hundred ten had a NA-based induction therapy, and 61 patients had a non-NA-based induction therapy. After a median follow-up of 45.4 months, the 4-year overall survival (OS) and progression-free survival (PFS) from transplantation were 60.5 and 25.5 %, respectively, for the NA-based induction group and 54.6 and 15.6 %, respectively, for the non-NA-based induction group. Multivariate analyses revealed that the patients who had NA-based induction had a significantly shorter OS (P < 0.001) and PFS (P < 0.001) when at least a partial response (PR) was not achieved. In patients who did not receive NAs before ASCT, lack of at least a PR to induction therapy was not associated with a survival disadvantage. These findings suggest that, unlike pretransplantation induction before NAs, patients who do not respond to induction treatment using NAs may not derive a benefit from ASCT. The relevance of induction failure differs for corticosteroid- and NA-based induction.

Outcome of patients with acute lymphoblastic leukemia (ALL) following induction therapy with a modified (pulsed dexamethasone rather than continuous prednisone) UKALL XII/ECOG E2993 protocol at Tawam Hospital, United Arab Emirates (UAE).

This retrospective data analysis examined the outcome of 99 acute lymphoblastic leukemia (ALL) patients treated at Tawam Hospital between January 2000 and December 2009. Sixteen patients were treated before June 2002, and 83 patients were treated from June 2002. A modified form of UKALL XII/ECOG E2993 with pulsed dexamethasone in induction phase one (modified UKALL) was the main therapy from June 2002 (71/83). The median age was 28 years. Fifty-eight percent had pre-B ALL where 36 % of them were Philadelphia chromosome-positive (Ph+). Overall, complete remission (CR) rate was 86.7 % which was significantly inferior for patients with white blood cell count 30-100 × 109/l (p = 0.009), therapy before June 2002 (p = 0.02), pregnancy (p = 0.005), CNS leukemia (p = 0.028), and unknown karyotype (p = 0.004). With a median follow-up of 11.8 months (0.49-126 months), the estimated overall survival (OS) and event-free survival (EFS) at 3 years were 50.6 and 28.7 %, respectively. OS and EFS were significantly inferior for patients not in CR after induction, age >20 years, Ph+, unknown karyotype and therapy before June 2002. In addition, CR, OS and EFS were significantly superior (p = 0.004, p < 0.001 and p = 0.001, respectively) for therapy with our modified UKALL protocol compared to Tawam protocol (main therapy before June 2002). In conclusion, the outcome of treatment for ALL at our institute is encouraging with significant improvement in the outcome of older adolescents and young adults when using high-intensity chemotherapy. This suggests that such an approach is feasible in developing countries in spite of some limitations including lack of stem cell transplantation service.

Induction chemotherapy for locoregionally advanced head and neck cancer: past, present, future?

The treatment of patients with locoregionally advanced squamous cell cancer of the head and neck is still evolving. Induction chemotherapy (IC) is widely used in this patient population and it is unclear how to best incorporate IC into multimodality treatment. Recently, the results of two randomized clinical trials were presented (the PARADIGM and Docetaxel Based Chemotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer trials), which showed no demonstrable benefit of IC followed by concurrent chemoradiation over concurrent chemoradiotherapy alone. However, a lower rate of distant metastatic disease was noted, suggesting that patients who are at high risk for metastatic disease may benefit from IC. This review summarizes how IC has evolved over the years, provides an update of recent developments, and discusses how IC may develop in the future.

New aspects of induction chemotherapy for head and neck cancer: POSTASCO 2011.

Treatment options of patients with advanced head and neck cancer developed in the last years. Surgical approaches with or without radiotherapy used to be the standard therapy for a long time. Calls for organ preservation, poor overall survival and unsatisfactory quality of life made changes in this therapy regime necessary. Systemical approaches were evaluated, first concepts of platinum-based chemotherapy paired with 5-fluorouracil (PF) made up the basis of induction chemotherapy (ICT). Hypothesized advantage of this regime was improvement in local and distant tumor responsiveness with an acceptable toxicity profile. Further investigations proved the addition of docetaxel (TPF) superior to PF, which presents the gold standard of current induction chemotherapy regimes. Long-term results underlining well-known aspects of this regime as well as new approaches of induction chemotherapy were published at ASCO 2011, including the addition of bioimmunotherapy to radiotherapy, adding nanoparticle-bound albumin to chemotherapy and investigations in toxicity reduction. Further investigations are still made not only to increase survival outcomes and local control but also to improve quality of life by reducing acute and late toxicities.

Advances in therapies for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor α (RARα) and the promyelocytic leukemia (PML) gene. The resultant PML-RARα fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARα fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients.