Paolo Indolfi

Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management.

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardiotoxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children.It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF.In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction.The beneficial effects of β-adrenoceptor antagonists (β-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.

Recent Advances in the Prevention of Anthracycline Cardiotoxicity in Childhood

The prevention of anthracycline cardiotoxicity is particularly important in children who can be expected to survive for decades after cancer chemotherapy with these agents. The rapid increase in clinical toxicity at doses greater than 550 mg/m(2) of doxorubicin (DOX) has made this dose the limiting one in order to avoid DOX-induced cardiac failure. However, arbitrary dose limitation is inadequate because of variability of individual tolerance. Decreasing myocardial concentrations of anthracyclines (ANT) and their metabolites and schedule modification of administration can reduce anthracycline cardiotoxicity. Anthracycline structural analogues such as epirubicin, idarubicin and mitoxantrone have been used in clinical practice. In addition, the liposomal ANT, which can be incorporated into a variety of liposomal preparations, are a new class of agents that may permit more specific organ targeting of ANT, thereby producing less cardiac toxicity. Much interest has focused on the administration of ANT in conjunction with another agent that will selectively attenuate the cardiotoxicity. As is known, the ANT chelate iron and the DOX-iron complex catalyzes the formation of extremely reactive hydroxyl radicals. Many agents, such as dexrazoxane (DEX), able to remove iron from DOX, have been investigated as anthracycline cardioprotectors. Clinical trials of DEX have been conducted in children and significant short-term cardioprotection with no evidence of interference with antitumor activity has been demonstrated. Whether long-term cardiac toxicity will also be avoided in surviving patients has not yet been determined.

A prospective protocol for nasopharyngeal carcinoma in children and adolescents: The Italian Rare Tumors in Pediatric Age (TREP) project

Nasopharyngeal carcinoma (NPC) is very rare in childhood. It differs from its adult counterpart in the prevalence of the nonkeratinizing, undifferentiated subtype and by an advanced clinical stage at onset and better chances of survival. The risk of long‐term treatment‐related toxicity also may be a more important issue in younger individuals.

Prognostic factors in pleuro‐pulmonary blastoma

To evaluate the prognostic factors in a series of children affected by pleuropulmonary blastoma (PPB).

Rhabdomyosarcoma in adolescents: A report from the AIEOP Soft Tissue Sarcoma Committee

In many types of cancer, the survival rates are reported to be less favorable for adolescents compared with younger children. To investigate whether this is true for adolescents with rhabdomyosarcoma (RMS), the results obtained in patients enrolled in protocols run by the Italian Soft Tissue Sarcoma Committee (STSC) were analyzed.

Prognostic role of bcl-xL and p53 in childhood acute lymphoblastic leukemia

Molecular parameters involved in the prediction of response of childhood acute lymphoblastic leukemia (ALL) are still unclear. We have evaluated the expression and mutational status of p53 and the expression of bcl-xL and bax in a series of 62 consecutive children (median age: 4 years; 38 males and 24 females) affected by de novo ALL. Alterations and overexpression of p53 were uncommon events (9/62, 14.5%) while bcl-xL and bax overexpression were frequent (about 70%). EFS was directly correlated to age < 6 years (p= 0.0178), non-T phenotype (p= 0.0470), WBC at diagnosis < 20000/µl (p= 0.0093), response to induction therapy with prednisone (p= 0.0211) and inversely correlated to mutated p53 or overexpression of p53 (p= 0.0039) and high intensity of BclxL expression (p= 0.0055). OS was directly correlated with age < 6 years (p= 0.0004), female gender (p= 0.0139), non-T phenotype (p= 0.0012), WBC at diagnosis < 20000/µl (p= 0.0187), response to induction therapy with prednisone (p= 0.0211), wild type p53 or low expression of p53 (p= 0.035). When all factors were considered in a stepwise Cox regression analysis, only the good response to PDN (p= 0.013) and the low intensity of Bcl-xL expression (p= 0.001) were independent significant prognostic factors with regard to EFS. Moreover, only age (p= 0.022), gender (p= 0.036) and WBC at the diagnosis (p= 0.050) were independent prognostic factors with regard to OS. Moreover, the mutated status of p53 was statistically correlated to the resistance to the induction therapy with PDN (correlation coefficient: - 0.349, p = 0.008). In conclusion, both bcl-xL and bax were frequently expressed at high intensity, but only bcl-xL was an independent predictor of EFS in our series. Moreover, p53 alterations were uncommon and alone not strong independent predictors of outcome, but they were correlated to poor response to therapy with PDN and inversely correlated to EFS and OS in univariate analysis.

Cardiac toxicity after anthracycline chemotherapy in childhood.

The clinical use of anthracyclines, a family of chemotherapeutic agents with efficacy against many solid tumors and leukemias is limited by unique cumulative dose-limiting cardiotoxicity. Overt heart failure occurs in 4.5% to 7% of patients treated with anthracyclines and the incidence of cardiac function abnormalities increases with the time. Anthracycline-induced congestive heart failure is usually due to permanent changes in the myocardium, changes most consistent with the contractile failure of cardiomyopathy. Although the causes of anthracycline-induced cardiotoxicity are probably many, a large body of evidence points to free-radical-mediated myocyte damage. The risk of developing cardiac heart failure is modified by the presence of certain risk factors that reduce cardiac tolerance to anthracyclines. Age and female gender seem to have an important role in the anthracycline cardiotoxicity. This cardiotoxocity can be divided, on the base of when it started, into acute, subacute and progressive late, chronic form. Various invasive and non-invasive methods have been used to measure the extent of cardiac damage done. Depending on the sensitivity of the method employed, the proportion of hearts found to be damaged has varied widely. Attempts to ameliorate anthracycline cardiotoxicity have been directed toward: 1. decreasing myocardial concentrations of anthracyclines and their metabolites, 2. developing less cardiotoxic analogous, and 3. currently administering cardioprotectants to attenuate the effects of anthracyclines on the heart. Much progress has been made in terms of monitoring of clinical and subclinical anthracycline cardiotoxicity, finding alternative schedules, introducing special carriers of anthracyclines and using cardioprotecting agents. It is hoped that with all these effects and with results of ongoing and future trials, we will be able to reduce further or even eliminate anthracycline cardiotoxicity.ZusammenfassungIn der Klinik ist die Anwendung von Anthrazyklinen, eine Gruppe von chemotherapeutischen Substanzen mit guter Wirkung gegen solide Tumoren und bei Leukämie, limitiert, da bei steigender Dosierung eine kardiotoxische Wirkung auftritt. Eine manifeste Herzinsuffizienz wird bei 4,5 bis 7% der Patienten beobachtet, wenn sie mit Anthrazyklinen behandelt werden. Die Inzidenz von Herzerkrankungen steigt mit der Zeit der Verlaufsbeobachtung. Die Anthrazyklin-induzierte Herzinsuffizienz wird gewöhnlich durch reversible Veränderungen des Myokards hervorgerufen, die im Wesentlichen in einem Versagen der kardialen Leistungsfähigkeit des Herzens besteht. Derzeit wird als Hauptmechanismus eine Myozytenzerstörung durch freie Radikale diskutiert. Das Risiko der Herzinsuffizienz wird durch verschiedene Faktoren verändert, die die kardiale Toleranz in Bezug auf Anthrazykline verändern können. Das Alter und auch das Geschlecht haben eine besondere Bedeutung bei der Entwicklung der Anthrazyklin-Kardiotoxizität.Die Kardiotoxizität nach Anthrazyklin wird unterschieden in eine akute, subakute und eine progressiv latente chronische Form. Verschiedene invasive und nicht-invasive Methoden sind eingesetzt worden, um die sich entwickelnde Funktionsstörung aufzudecken, allerdings ohne bisher eine Methode der Wahl gefunden zu haben.Verschiedene Ansätze wurden gewählt, um die Anthrazyklin-induzierte Kardiotoxizität zu reduzieren: 1. Reduktion der Myokardkonzentration von Anthrazyklin und Metaboliten, 2. Entwicklung von weniger kardiotoxischen Analoga, 3. Gabe von protektiven Medikamenten gegen die Wirkung von Anthrazyklin.Wesentlich war die Entwicklung von speziellen Trägersubstanzen für Anthrazykline und der Einsatz von kardioprotektiven Substanzen. Es bleibt zu hoffen, dass eine weitere Reduktion der Anthrazyklin-Kardiotoxizität in Zukunft gelingt.

Local Lymph Node Involvement in Pediatric Renal Cell Carcinoma: A Report From the Italian TREP Project

One of the most important adverse prognostic factors for adult renal cell carcinoma (RCC) is the retroperitoneal lymph node involvement. The aim of this article is to study the prognostic significance of local lymph node involvement in pediatric RCC and the role of retroperitoneal lymph node dissection (RLND) at diagnosis.

Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry

Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00–12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38–21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20–20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38–38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55–10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74–16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90–753.20) and soft tissue (SMR 453.00, 95% CI 203.50–1008.40), small intestine (SMR 1375.50, 95% CI 344.00–5499.70), nasal cavity (SMR 13.71, 95% CI 1.93–97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2–127.55)

Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma

AIM The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma. PATIENTS AND METHODS Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered. RESULTS Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years. CONCLUSION Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.