Doxorubicin-treated Patients Research Articles

Role of mitochondria in doxorubicin-mediated cardiotoxicity: From molecular mechanisms to therapeutic strategies.

This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control, including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.

Best Overall Response-Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.

This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation. A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e-7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.

This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control (MQC), including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.

Protective Effect of Omega-7 against Doxorubicin-Induced Cardiotoxicity in Male Rats

Background: Doxorubicin is considered one of the most effective anticancer drugs, yet it is use is limited by its side effect mediated by the generation of reactive oxygen species. Omega-7, an antioxidant has shown to have a cardioprotective effect.
 Aim of the study: evaluate a possible protective effect of omega-7 against doxorubicin-induced cardiotoxicity in male rats.
 Methods: twenty-eight male rats were divided into 4 groups (7 for each group). Group 1 (Negative control): healthy animals received normal saline orally as the vehicle for eight successive days and were sacrificed on day 9. Group 2 (positive control): animals that received a single dose of doxorubicin HCl (i.p 15mg/kg). Sacrificed the next day. Group 3: omega 7 was administered orally at a dose 100 mg/kg/day for eight days. On day 9, doxorubicin was administered IP (15mg/kg). Sacrificed on day 10. Group 4: omega 7 was administered orally at a dose 300 mg/kg/day for eight days. On day 9, doxorubicin was administered IP (15mg/kg) and sacrificed on day 10. Omega7 treatment started eight days before doxorubicin. The analysis was done on day 10.
 Results: In the present study, catalase, and glutathione peroxidase were significantly increased in the omega7 treated group when compared to the negative control group (p<0.05) at the same time, malondialdehyde and reactive oxygen species were significantly decreased in the omega7 treated group when compared to the negative control group (p<0.05).
 Conclusion: this in vivo enzymatic study provides a piece of evidence for the possible effect of omega7 in the attenuation of cardiac toxicity in doxorubicin-treated patients

Enabling Chemo-Immunotherapy with HIFU in Canine Cancer Patients.

High intensity focused ultrasound (HIFU) is a promising non-invasive technique for treating solid tumors using thermal and histotripsy-based mechanical ablation. However, its clinical significance in different tumor types is not fully understood. To assess its therapeutic efficacy and immunomodulatory properties, we compared HIFU thermal ablation and histotripsy ablation in dogs with spontaneous tumors. We also evaluated the ability of non-ablative HIFU-based mild hyperthermia (40-45 ºC) to improve Doxorubicin delivery and immunomodulation. Our results showed that HIFU thermal ablation induced tumor remission in the majority of treated patients over 60days, while histotripsy achieved partial response to stable disease persistence. The adverse effects of thermal ablation were minor to moderate, while histotripsy exposures were relatively well-tolerated. Furthermore, we observed a correlation between HIFU-therapeutic response and serum anti-tumor cytokine profiles and the presence of functionally active cytotoxic immune cells in patients. Similarly, Doxorubicin-treated patients showed improved drug delivery, efficacy, and anti-tumor immune responses with HIFU hyperthermia. In conclusion, our study demonstrates that depending on the tumor type and treatment parameters, HIFU treatments can enable tumor growth control, immune activation, and chemotherapy in veterinary patient. These findings have significant clinical implications and highlight the potential of HIFU as a promising cancer treatment approach.

Analysing the risk factors of doxorubicin-associated heart failure by a retrospective study of integrated, nation-wide databases

The incidence of dilated cardiomyopathy after anthracycline chemotherapy is mainly influenced by anthracycline cumulative dose. Previous researches showed doxorubicin treatment under cumulative dose of 450 mg/m2 associated with a low incidence of heart failure. Nowadays, doxorubicin is administered with a lower dose, the development of heart failure is largely determined by other factors. Our purpose was to identify the risk factors for heart failure due to doxorubicin therapy. With the use of the Hungarian financial healthcare databases merged with the National Cancer Registry, we performed a retrospective study. All the patients having confirmation for breast carcinoma between 2004 and 2015 were enrolled. The subjects with a preceding period characterized by any chemotherapy or diagnoses suggesting heart failure were excluded. Heart failure outcome event was defined by the assignment of I50 diagnosis code at hospital discharge or in autopsy reports. We used multivariate binary logistic regression to calculate odds ratios for heart failure. Besides the baseline characteristics, oncological state and cumulative doses of the chemotherapies were also taken into account. Among the analysed 3288, doxorubicin-treated patients, heart failure cumulative incidence was 6.2%. Doxorubicin cumulative dose over 400 mg/m2 increased the risk. The heart failure incidence was essentially influenced by age, even over 50 years the risk rose. Diabetes mellitus and the treatments with pyrimidine-analogues, carboplatin or bevacizumab were also associated with higher risk. By the integration of national financial and clinical databases, we could identify the risk factors for doxorubicin-associated heart failure. Orv Hetil. 2020; 161(26): 1094-1102.

White Adipose Tissue and Cancer: Impacts of Doxorubicin and Potential Co-Therapies

Abstract Background: White adipose tissue is an essential reservoir of energy that stores and releases fatty acids and secretes hormones, inflammatory cytokines and adipokines in health and cancer. The adipose tissue modulates cancer development and treatment, affecting responsiveness to chemotherapy, quality of life and survival. In addition, adipose tissue is damaged by doxorubicin, which is a non-selective anticancer drug widely used in clinical practice. Aim: This review was focused on the relevance of the white adipose tissue and how it can be affected by doxorubicin and cancer, the mechanisms involved and possible co-therapies that improve white adipose tissue functions. Scope of review: Adipose tissue complexity can influence cancer development, treatment and survival. The adipose tissue secretes adipokines that have paracrine and endocrine effects and may influence tumourigenesis, survival and quality of life in patients with cancer. The chemotherapeutic drug doxorubicin promotes deep impact on the adipose tissue, inhibiting adipogenesis and lipogenesis. Doxorubicin also causes downregulation on peroxisome proliferator-activated receptor gamma (PPARγ) and 5' adenosine monophosphate-AMP-activated protein kinase (AMPK) signalling in white adipose tissue, affecting lipid and glucose metabolism. Some alternative therapies, such as metformin, pioglitazone and physical exercise may contribute to mitigate side effects of doxorubicin. Conclusion: White adipose tissue has a complex and intricate role on cancer and is deeply affected by doxorubicin leading to a deep impact on adipose tissue function and worse quality of life. Potential co-therapies to prevent the side effects of doxorubicin should be studied to improve the quality of life of doxorubicin-treated patients.

Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer.

Anthracyclines are amongst the most effective chemotherapeutics ever developed, but they produce grueling side-effects, serious adverse events and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular Prion protein (PrPC), blocking their cytotoxic activity. This effect was dose-dependent using either cell line-conditioned medium or human serum as a source of PrPC. Genetic depletion of PrPC or inhibition of binding via chelation of ionic copper prevented the interaction and restored cytotoxic activity. This was more pronounced for doxorubicin than its epimer, epirubicin. Investigating the relevance to breast cancer management, we found that the levels of PRNP transcript in pre-treatment tumor biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly amongst doxorubicin-treated patients with residual disease at surgery (p=2.8E-08). These data suggest that local sequestration could mediate treatment resistance. Consistent with this, tumor cell expression of PrPC protein correlated with poorer response to doxorubicin but not epirubicin in an independent cohort analyzed by immunohistochemistry, particularly soluble isoforms released into the extracellular environment by shedding (p=0.015). These findings have important potential clinical implications for frontline regimen decision-making. We suggest there is warranted utility for prognostic PrPC/PRNP assays to guide chemo-sensitization strategies that exploit an understanding of PrPC-anthracycline-copper ion complexes.

The Endogenous Lusitropic and Chronotropic Agent, B-Type Natriuretic Peptide, Limits Cardiac Troponin Release in Cancer Patients with an Early Impairment of Myocardial Relaxation Induced by Anthracyclines.

We have reported that cancer patients treated with anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone B-type natriuretic peptide (BNP). Post-hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained normal relaxation. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction, but high BNP levels resulted in positive chronotropism and inappropriate tachycardia. Some patients developed increased circulating levels of cardiac troponin I isoform (cTnI), a marker of cardiomyocyte necrosis. Here we have characterized whether cTnI elevations correlated with diastolic dysfunction that manifested as impaired relaxation or a high level of BNP. The effects of high BNP levels on cTnI elevations were also characterized. We show that impaired relaxation or high BNP levels were significantly more frequent in patients with cTnI elevations. High BNP levels diminished the plasma peak and area under the curve of cTnI, but this result was accompanied by inappropriate tachycardia. cTnI elevations occurred only in patients treated with anthracyclines; moreover, the association of impaired relaxation or high BNP levels with cTnI elevations was significantly more frequent in doxorubicin-treated patients compared with patients treated with its analog, epirubicin. These findings describe cause-and-effect relations between impaired relaxation and cardiomyocyte necrosis, illuminate the role of anthracycline analogs, denote that the beneficial effects of BNP in relieving impaired relaxation and cardiomyocyte necrosis are counterbalanced by inappropriate tachycardia. Patients showing troponin elevations and impaired relaxation or high BNP levels should be treated with lusitropic drugs that lack a positive chronotropism.

Pesticide-induced immunotoxicity: the experience at EFSA

Doxorubicin (Dox) is limited in its use because of its adverse effect of inducing irreversible heart dysfunction. Innate immune factors, including toll-like receptors (TLRs), play important roles in most cardiac diseases and doxorubicin-induced cardiotoxicity. In this study, subjects were divided into the following groups: healthy controls (n = 62), HF group (n = 60), Dox group (n = 82), and Dox-HF group (n = 32). Expressions of TLR mRNAs in peripheral blood mononuclear cells were detected by RT-PCR. Western blotting was used to quantify protein expressions of Peripheral blood mononuclear cells (PBMCs) TLRs and their downstream signal proteins. The release of inflammatory factors was detected by ELISA. Results indicated that TLR2 was increased and TLR3 was decreased between the control group and Dox group, and between the Dox group and Dox-HF group. Serum inflammatory factors were comparable between the HF group, the Dox group, and the Dox-HF group. This study suggested that TLR2 and TLR3 are up- and down-regulated, respectively, in doxorubicin-treated patients who develop heart dysfunctions. This may suggest a predictive role for TLR2-TLR3 imbalance in doxorubicin-induced heart failure.

TLR2 and TLR3 expression as a biomarker for the risk of doxorubicin-induced heart failure

Doxorubicin (Dox) is limited in its use because of its adverse effect of inducing irreversible heart dysfunction. Innate immune factors, including toll-like receptors (TLRs), play important roles in most cardiac diseases and doxorubicin-induced cardiotoxicity. In this study, subjects were divided into the following groups: healthy controls (n = 62), HF group (n = 60), Dox group (n = 82), and Dox-HF group (n = 32). Expressions of TLR mRNAs in peripheral blood mononuclear cells were detected by RT-PCR. Western blotting was used to quantify protein expressions of Peripheral blood mononuclear cells (PBMCs) TLRs and their downstream signal proteins. The release of inflammatory factors was detected by ELISA. Results indicated that TLR2 was increased and TLR3 was decreased between the control group and Dox group, and between the Dox group and Dox-HF group. Serum inflammatory factors were comparable between the HF group, the Dox group, and the Dox-HF group. This study suggested that TLR2 and TLR3 are up- and down-regulated, respectively, in doxorubicin-treated patients who develop heart dysfunctions. This may suggest a predictive role for TLR2-TLR3 imbalance in doxorubicin-induced heart failure.

Prevention of palmoplantar erythrodysesthesia in patients treated with pegylated liposomal doxorubicin (Caelyx®).

Palmoplantar erythrodysesthesia (PPE) is one of the most frequent side effects during systemic treatment with pegylated liposomal doxorubicin (PLD, Caelyx®). PPE lesions show a range of symptoms, from numbness to painful erosions, and can have a major impact on the quality of life in affected patients. Previously, a possible pathomechanism of PPE was found in doxorubicin-treated patients based on radical formation in the skin. Here, a preventive strategy using a topically applied ointment with a high radical protection factor was investigated. In this randomized placebo-controlled double-blind study the antioxidant-containing ointment was compared with a placebo ointment regarding PPE grade III occurrence, overall PPE grade I-III occurrence and PPE severity in PLD patients. The verum or placebo cream was topically applied for a period of 16weeks, starting 3days prior to the first cycle of chemotherapy. Clinical evaluations were carried out by a dermatologist prior to the first cycle of chemotherapy and every 4weeks for the duration of 16weeks. Thirty-two patients were enrolled in total, of which 17 (66%) completed the study. No PPE grade III was found in the verum group, while five out of seven patients (71%) had to be unblinded in the placebo arm due to PPE grade III (p=0.003). General PPE occurrence of all grades was 60% under verum and 86% under placebo treatment. The preventive application of an antioxidant-containing ointment was shown to be significantly more effective in the prevention of PPE grade III compared to placebo treatment.

Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS).

9503 Background: Anthracyclines are highly efficacious in OS but associated with risk of cardiotoxicity. We conducted two studies using dexrazoxane as a cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) P9754, a series of pilot studies including doxorubicin dose intensification in patients with localized OS. Methods: Patients on AOST0121 received methotrexate, doxorubicin (375 mg/m2), cisplatin, ifosfamide and etoposide (MAPIE). Those with HER2-positive tumors also received trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 mg/m2 or 600 mg/m2 with each dose preceded by dexrazoxane (10:1 ratio). Etoposide was never given simultaneously with dexrazoxane. Measurements of left ventricular systolic function by echocardiography, serum troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained at baseline and repeated during therapy. Secondary malignancies were reported to the NCI. Results: None of the 47 patients (17 receiving trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant changes in left ventricular fractional shortening, measurable cTnT, elevation of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 patients treated on AOST0121 and two of 272 patients on P9754 developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This large group of OS patients demonstrates that dexrazoxane is an effective cardioprotectant for doxorubicin alone (375-600 mg/m2), and in combination with trastuzumab. Dexrazoxane did not lead to an increase in secondary malignancies in OS patients treated with these regimens as compared to historical rates of 1-2%. Our results do not support the findings of a recent European Medicines Agency safety review that concluded dexrazoxane was unsafe for use in children and adolescents due to risk of SMN.

Doxorubicin, Cardiac Risk Factors, and Cardiac Toxicity in Elderly Patients With Diffuse B-Cell Non-Hodgkin's Lymphoma

Anthracycline-based chemotherapy, which improves survival for patients with non-Hodgkin's lymphoma, is often withheld from elderly patients because of its cardiotoxicity. We studied the cardiac effects of doxorubicin in a population-based sample of older patients with diffuse large B-cell lymphoma (DLBCL). Among patients age > or = 65 years diagnosed with DLBCL from 1991 to 2002 in the Surveillance, Epidemiology, and End Results-Medicare database, we developed logistic regression models of the associations of doxorubicin with demographic, clinical, and cardiac variables. We then developed Cox proportional hazards models of the association between doxorubicin and subsequent congestive heart failure (CHF), taking predictors of CHF into account. Of 9,438 patients with DLBCL, 3,164 (42%) received doxorubicin-based chemotherapy. Any doxorubicin use was associated with a 29% increase in risk of CHF (95% CI, 1.02 to 1.62); CHF risk increased with number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension; hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio = 1.8; P < .01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in doxorubicin-treated patients versus 79% in patients not treated with doxorubicin. Among patients receiving chemotherapy for DLBCL, those with prior heart disease were less likely than others to be treated with doxorubicin, and those who received doxorubicin were more likely than others to develop CHF. Various cardiac risk factors increased CHF risk, but only hypertension was synergistic with doxorubicin. Doxorubicin has dramatically improved survival of DLBCL patients; nonetheless, some subgroups may benefit from efforts to reduce doxorubicin-related CHF risk.

Reply:

We agree that a high hepatitis B virus (HBV) load prior to treatment is not the only but one of the significant adverse prognosticators for survival in patients with hepatocellular carcinoma (HCC) with chronic HBV infection undergoing chemotherapy.1 In response to the comment by Huo et al., analysis was conducted with incorporation of Cancer of the Liver Italian Program (CLIP) scores2 in our studied patient population. Upon univariate analysis, CLIP was found to be another prognosticator for survival in addition to the already reported pretreatment factors. Upon multivariate analysis, the factors significantly affecting survival were, again: total bilirubin (P = 0.0020; HR [hazard ratio] = 1.040 for every 1 μmol/L rise in level, 95% confidence interval [CI], 1.014-1.066), hepatitis C virus (HCV) infection (P = 0.0040; HR = 8.794, 95% CI, 2.003-38.616), high HBV DNA level (P = 0.0319; HR = 1.596, 95% CI, 1.041-2.447), and CLIP was also found to affect survival (P = 0.0030, HR = 1.314, 95% CI, 1.097-1.574). In the coexistence of HCC-related and HBV-related chronic liver disease, it is acknowledged that the cause of death for HCC patients cannot be completely attributable to the malignancy per se. Similarly, morbidities during and after chemotherapy in HCC patients cannot solely be attributable to treatment-related complications. As such, although the authors concluded that the causes of death were due to malignancy in 76% of the cases, and treatment-related complications in 6% of the cases, it would be highly unlikely that one could rule out HBV-associated chronic liver disease as an important contributing factor to the mortality and morbidity in our patient population. In the exploratory analysis, patients who developed severe hepatitis appeared to have the worst survival; this difference in clinical outcome was not found to be statistically significant and as discussed, this was presumably due to the relatively small number studied. However, the main objective of this part of the analysis remains hypothesis-generating, and a conclusive verdict could not be derived from analysis that remains exploratory. Interferon was included in PIAF chemotherapy (other agents included were cisplatin, doxorubicin and 5-fluorouracil) for its immunodulatory, antiproliferative and antiangiogenic effects.3 As discussed in our article, the dosage of interferon in the PIAF regimen was much lower than that used for the treatment of chronic HBV infection. Furthermore, conventional interferon had been shown to be less effective in Asian chronic HBV infection. Thus, it is unlikely to have a therapeutic effect on the chronic HBV infection in our HCC population, and is supported by the fact that rate of hepatitis was the same in both chemotherapy arms. The median baseline HBV DNA in PIAF-treated versus doxorubicin-treated patients were similar at 106.25 and 106.81 copies/mL, respectively; there was no difference in the rate of severe hepatitis between the 2 group of patients. In conclusion, the present study demonstrated that a high HBV load prior to treatment is one of the significant adverse prognosticators for survival in HCC patients with chronic HBV infection undergoing chemotherapy. It is our opinion that the data support the adoption of antiviral agents as part of the supportive therapy in an attempt to improve survival of these patients. Winnie Yeo*, Frankie K. F. Mo*, * Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, China.

Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without Compelling Evidence

TO THEEDITOR: The title of a recent article by Tebbi et al 1 claims that dexrazoxane poses a risk, and that it is responsible for a higher incidence of secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and other second malignant neoplasms (SMNs) in children with Hodgkin’s disease (HD) treated with dexrazoxane plus doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC) as well as radiotherapy (POG 9426 [low-stage HD] and 9425 [advanced-stage HD]). This claim is based on 10 SMNs (including eight AML/MDS) in 478 patients. Differences in the incidence of SMNs between children randomly assigned to receive dexrazoxane versus no dexrazoxane concomitantly with chemotherapy to evaluate its efficacy as a cardiopulmonary protectant show no statistical significance by simple Fisher’s exact tests (of 239 patients, eight [3.35%] v two [0.84%] with SMNs, respectively, and P .11; six [2.51%] v two [0.84%] with AML/ MDS, respectively, and P .24), nor by the more conventional and appropriate time-to-event analysis used by the authors (P .06 for SMNs;P .16 for AML/MDS). Only after adjusting for race, age, and sex in a different analysis using a Poisson regression model were the authors able to achieve aP value below .05 for any type of SMN (P .02 for SMNs; P .10 for AML/MDS), even though the authors demonstrated no imbalance between arms for race, age, or sex. We would regard this as scant statistical evidence, particularly in a trial that, as the authors observe, was not “designed for statistical comparison of leukemia and SMN risk.” 1 Dexrazoxane is a US Food and Drug Administration–approved, established protectant against doxorubicin-induced cardiotoxicity in patients with breast cancer 2 and is also cardioprotective in acute lymphoblastic leukemia of childhood, 3 as well as with other malignancies. 4 No evidence shows that this protection has impaired the effectiveness (survival) of doxorubicin-treated patients or that it has caused any new or clinically relevant sequelae (infection, hemorrhage, deaths, or necessity for change of dosage). Some 16 clinical trials in seven different countries over the past 10 years involving more than 500 patients have not reported a single case of AML as a result of combining dexrazoxane with doxorubicin plus fluorouracil and cyclophosphamide (the FAC regime). 4

Detection of Proteins Related to Therapeutic Outcome, Including Drug Resistance, in Acute Myeloid Leukemia Using Mass Spectrometry and Gel Based Proteomic Profiling.

To further improve and individualize curative treatment approaches for patients with AML, novel proteins and protein functions need to be discovered. In particular, the mechanisms responsible for chemotherapy resistance appear essential to unravel. Clinical proteomics may help to provide such information. We have used a chip-based technique, surface enhanced laser desorption/ionization mass spectrometry (SELDI-MS), to compare protein expression profiles in AML. With this technique proteins in the molecular weight area of 2–40 kDa can be spotted. For selected samples, a two-dimensional electrophoresis (2DE) method was employed, allowing detection of proteins between 15–120kDa. In the first part of the study, mononuclear peripheral blood cells were obtained from 8 AML patients clinically sensitive to and 7 patients clinically resistant to doxorubicin-containing induction chemotherapy. The clinical outcome correlated to results from parallel in vitro drug testing using the FMCA method. In addition, two variants of the human leukemic cell line CEM, one sensitive and one resistant to teniposide (CEM/VMI), were analysed. In the second part of the study, global proteomic profiles from 24 selected AML patients with good vs. poor clinical outcome (remission duration) were investigated. A total of 812 proteins were detected in the mononuclear cells obtained from the 15 doxorubicin-treated patients. Twenty of these proteins were distinguished as different between the sensitive vs. resistant patient groups. Assessing the CEM cell lines by utilizing four different affinity surfaces on ProteinChip™ arrays, approximately 450 peptides and proteins were detected. Between 29 and up to 65 proteins were detected as differentially expressed between the sensitive and the resistant CEM variants. Using the 2DE technology, approximately 1000 spots were matched on the CEM cell lines, with 47 clear expression level differences between the sub cell lines. In clustering analysis using the protein profile data we could demonstrate clear clustering of sensitive and resistant patient and cell line cells according to sensitivity measurements (IC50). Using these methods we have selected a panel of putative resistance related proteins, which are currently being identified and validated. Data from the second phase of the study, derived from 24 selected AML cell populations, are presently being analyzed. In conclusion, significant differences in protein profile expression were observed between cells obtained from AML patients with clinically divergent treatment responses. Further studies aim at identifying key proteins and protein functions to allow for improved therapeutic efficacy.

Topoisomerase-IIα expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel

Abstract Purpose: The predictive value of topoisomerase-IIα (topo-II) has been evaluated in advanced breast cancer patients randomly treated with single-agent doxorubicin or docetaxel. Experimental design: Primary tumor samples from patients enrolled in a randomized, phase III clinical trial comparing single-agent doxorubicin (75 mg/m2 q3wks) with docetaxel (100 mg/m2 q3wks) were collected and topo-II status was evaluated by immunohistochemistry (clone KiS1). Results: Topo-II status was evaluated in 108 samples, 55 (51%) in the doxorubicin arm and 53 (49%) in the docetaxel arm. An increment of 10% in cells expressing topo-II is associated with a statistically significant odds ratio (OR; 95% confidence interval) of 1.09 (1.03–1.15; P = 0.002) for overall response to doxorubicin versus 1.002 (0.94–1.07; P = 0.95) in the docetaxel arm. With increasing topo-II, the favorable OR for overall response to docetaxel compared with doxorubicin decreases to become not significant in patients with topo-II tumor content &amp;gt;10%. In a multivariate analysis, (a) HER-2 status seems positively correlated with overall response to chemotherapy (OR, 2.34; 95% confidence interval, 0.87–6.27; P = 0.09). (b) Overall response to doxorubicin is significantly lower than overall response to docetaxel (OR, 0.17; 95% confidence interval, 0.04–0.64; P = 0.009) but with a significant interaction term for doxorubicin-treated patients with topo-II tumor content &amp;gt;10% (OR, 8.31; 95% confidence interval, 1.86–37.03; P = 0.05). Conclusions: (a) Topo-II overexpression confers a higher probability of response in the doxorubicin arm only. (b) Despite being a small retrospective study, this study is in line with previously reported studies and the hypotheses raised are now being tested in a prospective neoadjuvant trial.

Myocardial performance index combining systolic and diastolic myocardial performance in doxorubicin-treated patients and its correlation to conventional echo/Doppler indices.

This study was designed to evaluate the utility of myocardial performance index (MPI) in anthracycline cardiotoxicity. The MPI measures the ratio of total time spent in isovolumic activity (isovolumetric contraction time and isovolumetric relaxation time) to the ejection time, thus giving a global index combining systolic and diastolic myocardial performance. In this study, MPI was measured in 35 doxorubicin-treated children (aged 108.5+/-55.31 months, 23 males and 12 females) in sinus rhythm and 32 age-matched controls, and it was compared with conventional Doppler echocardiographic parameters. The isovolumetric contraction time was prolonged (38.37+/-24.43 vs 26.37+/-15.53, p <0.02) and ejection time was shortened (231.91 +/- 28.87 vs 256.21+/-19.55, p<0.001) in doxorubicin-treated patients compared to that in normal children. The isovolumetric relaxation time did not show significant difference between patients and control group (60.11+/-10.92 vs 61.06+/-12.12, p>0.05). MPI was significantly increased in doxorubicin-treated patients compared with that in control groups (0.42+/-0.07 vs 0.34+/-0.06, p<0.001), and significant correlation was observed between MPI and fractional shortening, ejection fraction, and left ventricular end diastolic and end systolic diameters (respectively, r = -0.508, p <0.002; r = -0.532, p<0.001; r = 0.467 p<0.005; r=0.606, p<0.001). Also, a weak correlation was found between MPI and duration of the disease and patient ages (r = 0.393, p < 0.02; r = 0.379; p < 0.02). However, there was no correlation between MPI and cumulative doxorubicin dose (r = 0.311, p > 0.05) and diastolic Doppler parameters in doxorubicin-treated patients. We think that MPI may be a useful parameter in monitoring left ventricular dysfunction in anthracyline-treated patients.