Cardiac changes with cyclophosphamide

Serial echocardiographic (ECHO) studies were obtained on 40 pediatric patients (pts) treated with ≥ 80 mg/kg cyclophosphamide (CPM) (range 80–200 mg/kg) in 1 week. Patients were treated for solid tumors and prior to marrow transplant. Echo changes ocurred in 10/13 pts who received CPM ≥ 170 mg/kg over four days, and in 11/19 pts who received 120–140 mg/kg dose over two days and who had previously received ≥ 100 mg/m² anthracyclines with or without radiation. No changes were seen in eight pts who had 80–160 mg/kg CPM and < 100 mg/m² anthracyclines. The observed changes occurred approximately 1 week after CPM and persisted for days to weeks. Pericardial effusion seen in 15 pts was successfully treated with furosemide in 13. Two died with hemorrhagic pancarditis. Other changes seen were increased end diastolic left ventricular diameter, decreased fractional shortening and abnormal left ventricular preejection period/ejection time ratios. Thus, cardiac effects of high dose CPM are not rare in children. Patients receiving ≥ 170 mg/kg CPM in 1 week or 120 mg/kg in 1 week after ≥ 100 mg/m² anthracyclines are at particular risk.     

Determination of the maximum tolerated dose of idarubicin when used in a combination chemotherapy program of reinduction of childhood ALL at first marrow relapse and a preliminary assessment of toxicity compared to that of daunorubicin: A report from the childrens cancer study group

An escalating-dose trial of idarubicin, used weekly for 3 doses in combination with vincristine, prednisone, and L-asparaginase (VPLI), to reinduce remission of childhood ALL at first bone marrow relapse was conducted by the Childrens Cancer Study Group (CCSG). The maximum tolerated dose (MTD) of idarubicin, used in the manner, was determined to be 12.5 mg/m²/dose. Twelve of 16 (75%) evaluable patients in first marrow relapse of ALL treated at a dose of 10 or 12.5 mg/m² entered a second complete remission, compared to 41 of 69 evaluable patients (59%) treated in a comparable way with daunorubicin (30 mg/m²) (VPLD). Prolonged myelosuppression was observed in both groups, but the frequency of documented bacterial sepsis and the duration of required hospitalization were greater among patients treated with idarubicin. No additional toxicity, specifically attributable to idarubicin, was observed at these doses.     

Sequential chemotherapy of advanced colorectal cancer with standard or high-dose methotrexate followed by 5-fluorouracil

Thirty patients with advanced measurable colorectal cancer were randomized to receive either methotrexate (MTX) 200 mg/m² or 40 mg/m², followed in four hours by 5-fluorouracil (5-FU) 600 mg/m². Patients receiving the higher dose MTX were given leucovorin rescue 24 hours later. Eight of 13 patients treated with 200 mg/m² MTX + 5-FU developed severe hematologic toxicity, leading to two toxic deaths. In addition, 9/13 developed mild azotemia, and three patients had severe gastrointestinal toxicity. No patients with prior chemotherapy responded to either regimen. Among those without prior chemotherapy, there were two of six and three of eight partial responses, respectively, in the 200 mg/m² and 40 mg/m² MTX regimens. Sequential 200 mg/m² MTX followed by 5-FU after four hours has unacceptable toxicity. Sequential treatment with standard dose MTX + 5-FU is tolerable and merits further study.     

Autologous bone marrow transplantation in the treatment of children and adolescents with advanced malignant tumors

Nineteen patients with advanced malignant tumors, less than 20 years old were treated with intensive chemotherapy (vincristine 2 mg/m² i.v. and adriamycin 60 mg/m² i.v. on day ?7; cyclophosphamide 45 mg/kg i.v. on days ?6 to ?3), total body irradiation (TBI, 600 rads on day ?1) and autologous bone marrow transplantation (ABMT, day 0). Prior to this procedure induction of complete or partial remission by conventional therapy was attempted. Ten patients had intra-abdominal non-Hodgkin's lymphoma (NHL); three, yolk sac tumor; three, Ewing's sarcoma; and three, neuroblastoma. The supportive care included reverse isolation, immunoglobulin 400 mg/kg i.v. q 2 weeks, cotrimoxazole per os, and cell support as needed. No correlation between the bone marrow dose and the time of hematological reconstitution could be established. Five of seven patients with intraabdominal NHL stage III (transplanted in first remission) are surviving disease-free for 5 +, 5 +, 20 +, 23 +, and 35 + months after ABMT. None of three patients with intra-abdominal NHL stage IV is surviving (two of them were transplanted in second remission). One of three patients with yolk sac tumor is surviving disease-free for 27+ months. There are no survivors among the patients with Ewing's sarcoma and neuroblastoma. Only one of 19 patients was lost due to therapeutic complications, while 12 died due to tumor. Regarding treatment results for advanced intra-abdominal NHL, the procedure described here is comparable to the best conventional regimens. In vitro methods for tumor cell eradication in the collected bone marrow might further improve the results of ABMT.     

A comparative trial of daunorubicin,cytosine arabinoside,and thioguanine,and a combination of the three agents for the treatment of acute myelocytic leukemia

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M² daily × 3, cytosine arabinoside and thioguanine 100 mg/M² each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M² given on dav 1 and cvtosine arabinoside plus thioguanine each given at a dose of 100 mg/M² every 12 hours for five days. All patients received cyclophosphamide 600 mg/M² followed in 24 hours by hydroxyurea 500 mg/M² every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M² daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M² of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.     

VP-16 + adriamycin vs. Adriamycin alone in advanced adenocarcinoma of the breast,phase II,a randomized trial: A southwest oncology group study

One hundred twenty-two patients with advanced adenocarcinoma of the breast were randomized to receive adriamycin (AD) alone or a combination of VP-16 plus lower dose adriamycin (VAD). The patients were stratified to good and poor risk. The starting dose (day 1) of AD was 60 mg/m² for good risk and 45 mg/m² for poor risk. The starting dose of the VAD combination for the good-risk patient was VP-16, 75 mg/m² daily × 5 plus adriamycin 35 mg/m². The poor-risk dose for VAD was VP-16, 50 mg/m² daily × 5 plus adriamycin, 30 mg/m² on day 1. The total dose of AD was 450 mg/m² on both arms. The patients who were on the VAD arm continued on VP-16 maintenance. Both arms were repeated every 21 days. There were 54 evaluable patients on the adriamycinarm and 52 evaluable patients on the VAD arm. Both arms were similar with regard to age, menopausal status, performance status, and prior hormonal therapy. More hematologic toxicity was seen in the adriamycin arm. Complete responses were observed on both arms, three (5%) with adriamycin and three (5%) with combination. Eleven (19%) and ten (18%) partial responses were observed with the adriamycin and VP-16 plus adriamycin, respectively. AD produced more stable disease than VAD (41% vs. 29%). Complete responses were seen only in the good-risk patients. Time to progression was delayed on the combination arm (P = 0.02). The survival in both arms was similar. The addition of VP-16 to adriamycin does not offer an important clinical advantage.     

Phase I trial of subcutaneous interleukin-1α in children with malignant solid tumors

Interleukin-1α (IL-1α) is myeloprotective in a variety of animal models of cancer chemotherapy and is similarly beneficial in adults treated with carboplatin, 5-fluorouracil, and after autologous bone marrow transplantation. There are no trials of this agent in children. Our purpose was to determine the toxicity and maximum tolerated dose (MTD) of recombinant human interleukin-1α (rhuIL-1α) in children with solid tumors receiving intensive cancer chemotherapy and to evaluate its myelo-protective effects. Cohorts of patients received rhuIL-1α in doses of 0.1–10 μg/m² for 4 days by subcutaneous injection prior to ICE chemotherapy (ifosfamide, 2 g/m²/day × 3, carboplatin targeted to an area under the curve of 8 mg/ml × min on day 1, and etoposide, 100 mg/m² daily for 3 days). Patients were randomized to receive rhuIL-1α before either the first or second course of therapy. After the MTD of rhuIL-1α was determined, an additional group of patients received rhuIL-1α at that dose immediately following ICE chemotherapy. The dose-limiting toxicities of rhuIL-1agr; in the 27 children tested comprised systemic symptoms of fever, chills, headache, and hypotension. The MTD was 3 μg/m²/day. There were no differences in chemotherapy-induced hematologic toxicity with increasing doses of rhuIL-1α or in comparisons before or after ICE chemotherapy. Although rhuIL-1α can be given safely to children receiving myelosuppressive chemotherapy, clinical usefulness would mandate a significant hematopoietic benefit in view of the troublesome side effects identified. We saw no evidence of a hematoprotective effect. Med. Pediatr. Oncol. 28:444–450, 1997. © 1997 Wiley-Liss, Inc.     

Phase II trial of 4′-deoxydoxorubicin (DxDx) in non-small cell lung cancer: A cancer and leukemia group B trial

Eighty-seven patients with histologically or cytologically proven non-small-cell carcinoma of the lung were treated with 4′-deoxydoxo-rubicin (DxDx) 30 mg/m² every 3 weeks. Three responses (4%), all partial, were observed. All responses occurred in patients with large-cell anaplastic lung cancer and none in squamous or adenocarcinoma histologies (P < 0.01). The durations of partial response for these three responders were 70, 198+ and 209+ days. The side effects noted were predominantly neutropenia, anemia, and weight loss. In three patients, declines in cardiac ejection fraction of 7%, 12%, and 23% occurred after cumulative drug doses of 150 mg/m², 150 mg/m², and 233 mg/m², respectively. 4′-Deoxydoxorubicin had little activity in non-small-cell lung cancer at the dose used in this study.     

Treatment combined with bone marrow transplantation for advanced neuroblastoma: An analysis of patients who were pretreated intensively with the protocol of the study group of Japan

One hundred and ten patients with advanced neuroblastoma were treated with the protocol of the Study Group of Japan between January 1985 and March 1991. Patients received six cyclic courses of regimen A₁, consisting of cyclophosphamide (1,200 mg/m²), vincristine (1.5 mg/m²), tetrahydropyranyl adriamycin (40 mg/m²), and cisplatin (90 mg/m²). Primary tumors and regional lymph node metastases were removed some time during the first six cycles of regimen A₁. After six cycles of A₁, the patients were divided into three groups. Patients in group 1 received alternating treatment with regimen B (cyclophosphamide and ACNU) and intensified A₁, and those in group 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A₁. Patients in group 3 were treated with supralethal therapy and bone marrow transplantation (BMT). Event-free survival rates at five years were 38.8% in the chemotherapy group (groups 1 and 2) and 50.0% in the transplant group (group 3). Because of the study design that was not in truly randomized fashion and because of the small number of patients in each risk group, it is indicated, though not concluded, that the transplant group had a better prognosis than the chemotherapy group in the cases with stage III disease or with amplified N-myc oncogene, based on the statistical calculations. Differences in survival rates for patients who underwent BMT when complete remission (CR) was achieved and for those who achieved CR but who did not undergo marrow transplant were statistically insignificant. BMT-related death occurred in 3 of 31 cases (9.7%) undergoing marrow transplant, and the causes of the death included hemorrhagic pneumonia, myocardial disturbance and hemorrhagic uremia. © 1995 Wi1ey-Liss Inc.     

Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: A Childrens Cancer Group study

Methotrexate (MTX) infusions of 500–1,000 mg/m² over 24 hours may improve survival and prevent relapse in children with acute lymphoblastic leukemia (ALL). Childrens Cancer Group (CCG) Study 139 compared weekly oral methotrexate 20 mg/m²/week (oral MTX) to MTX 500 mg/m² infused over 24 hours (IV MTX) three times during consolidation and every 6 weeks during maintenance in 164 children with intermediate-risk ALL, i.e., those patients over age 1 year with white blood cell count 10,000 to 49,999/ml and no bulky extramedullary disease. Median follow-up for CCG-139 exceeded 75 months. Thirty-four events occurred among 80 patients receiving IV and oral MTX and 36 events among 84 patients receiving oral MTX. Two children died during induction and one did not enter remission. Remission induction rate is 98%. There have been 26 marrow relapses, 11 combined marrow and extramedullary relapses, 24 CNS relapses, and five testicular or other relapses. The frequency and distribution of relapses does not differ between the two regimens. For the entire group, overall event-free survival (EFS) at 6 years is 57.9% (standard deviation = 4.0%) and actuarial survival is 80.0% (standard deviation = 3.3%). Of the 29 patients with isolated extramedullary relapse, 18 survive free of a second event, a median of 42 months from relapse. In contrast to other trials, this trial does not show that IV MTX in this dose and schedule offers an advantage over standard therapy for this group of children. © 1996 Wiley-Liss, Inc.     

Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma

Thirteen patients with recurrent medulloblastoma were treated with cyclophosphamide in association with Sargramostim. Cyclophosphamide was given at doses ranging between 1.0–2.5 g/m² daily for two doses. Sargramostim was given at a fixed dose of 250 μg/m² subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the ANC was more than 1,000 cells/μl for two consecutive days. A total of 33 courses were given with toxicity consisting of grade 4 neutropenia in all courses and grade 3–4 thrombocytopenia in 10 of 13 patients. There were no deaths related to infection or bleeding. Four patients were taken off study because of prolonged myelosuppression. Three of these patients were at the 2.5 g/m² level, and of these three, two developed lung toxicity (grades 2 and 4, respectively). One patient developed an allergic reaction following the first injection of Sargramostim and was also taken off study. Of 10 evaluable patients, there were 9 PR and 1 SD. We conclude that cyclophosphamide at a dose of 2.0 g/m²/day × 2 days q 4 weeks in association with Sargramostim demonstrates marked activity with acceptable toxicity in patients with recurrent medulloblastoma. © 1995 Wiley-Liss, Inc.     

Therapy of disseminated malignant melanoma with recombinant α 2b-interferon and piroxicam: Clinical results with a report of an unusual response-associated feature (Vitiligo) and unusual toxicity (diffuse pulmonary interstitial fibrosis)

Fifteen patients with disseminated malignant melanoma were treated with recombinant a 2b-interferon (20 mU/m² intravenously 5 days per week for 4 weeks and then 10 mU/m² subcutaneously tiw) and piroxicam (10 mg a day orally for 10 days prior to beginning interferon and daily thereafter). Two complete responses of soft tissue disease and stabilization of disease in two other patients were obtained. One complete response was associated with the development of vitiligo. One patient who had entered complete remission was removed from the study because of diffuse pulmonary interstitial fibrosis, believed due to therapy. The combination of α 2b-interferon and piroxicam offers no clinical advantage over the use of α 2b-interferon alone. © 1994 Wiley-Liss, Inc.     

Oxaliplatin and Doxorubicin for Relapsed or Refractory High-Risk Neuroblastoma

Patients with relapsed or refractory neuroblastoma have poor long-term survival. New therapeutic regimens are needed. Doxorubicin and cisplatin are commonly used in the treatment of high-risk neuroblastoma. Oxaliplatin, a platinum compound with a 1,2-diaminocyclohexan carrier ligand, is more potent than cisplatin with less nephrotoxicity and ototoxicity. We treated seven relapsed/refractory neuroblastoma patients using oxaliplatin (105–130 mg/m²) and doxorubicin (60–75 mg/m²) together with dexrazoxane (10 mg/mg of doxorubicin) administered intravenously every three weeks. Prolonged thrombocytopenia causing treatment delay was observed when oxaliplatin was administered at 130 mg/m². A reduced dose of oxaliplatin 105 mg/m² on day 1 with doxorubicin at 20 mg/m²/dose on days 1–3 was well tolerated. Sensory neuropathies were mild and transient. No cardiotoxicity was noted despite all patients having a history of prior anthracycline exposure. Best responses included 1 complete response, 1 partial response, 1 mixed response, 3 stable diseases. In our cohort of heavily pretreated relapsed and refractory neuroblastoma patients, the combination of oxaliplatin and doxorubicin demonstrated anti-tumor activity and merits further investigation.     

Vm-26 with prednisone and vincristine for treatment of refractory acute lymphocytic leukemia

Fifty-six children with refractory acute lymphocytic leukemia (ALL) were assessed for remission-induction responses to VM-26 (250 mg/m² per week) in combination with prednisone (40 mg/m² per day) and vincristine (1.5 mg/m² per week). Each child had been treated intensively with steroids, vincristine, daunorubicin and L-asparaginase. In fact, all patients had failed to respond to previous reinduction therapy with prednisone-vincristine or had relapsed while receiving vincristine. Our intent in this study was to test whether or not addition of VM-26 to prednisone-vincristine would overcome clinical resistance to these established agents. Complete remissions were induced in 17 patients (0.30) over 4 to 6 weeks. Five of these children, all clinically unresponsive to prednisone-vincristine alone, had complete remissions that lasted longer than 1 year; two remain in remission for 2 1/2 years and both are now off therapy. Myelosuppression, the most serious treatment complication, was documented in 20 of 26 evaluable patients. The median time to recovery of normal marrow function was 15 days. These results demonstrate further the potential of VM-26 in combined-drug treatment of refractory ALL. Whether the effectiveness of this combination represents potentiation of prednisone and vincristine activity by VM-26 or some other, as yet unidentified interaction, remains to be determined.     

Echocardiographic assessment of anthracycline cardiotoxicity in children

Adriamycin and daunomycin are highly effective anti-tumor agents but have been known to be cardiotoxic in dosages > 500 mg/m². Echocardiograms were performed in 54 pediatric patients with a variety of malignant diseases in an attempt to detect early evidence of anthracycline-induced cardiac toxicity. Thirty baseline studies were performed while 81 studies were done during and/or following anthracycline chemotherapy. Baseline left ventricular (LV) function was normal; shortening fraction = 34 ± 1% and percent heart rate predicted velocity of fiber shortening = 109 ± 3%. No significant reduction in LV performance occurred until cumulative doses exceeded 250 mg/m². Between 250 mg/m² and 450 mg/m² mean shortening fraction = 30 ± 1% (p < 0.025) and percent of predicted shortening velocity = 93 ± 4% (p < 0.005). Above 450 mg/m² a further significant decrease in LV function was noted: shortening fraction = 21 ± 3% and percent of predicted shortening velocity = 63 ± 10%. Two of the five patients in this group developed congestive heart failure. We currently recommend that echocardiograms be performed prior to the start of anthracycline therapy and repeated every 80 to 120 mg/m² until a cumulative dose of 250 mg/m² is reached. Thereafter, echocardiograms should be performed prior to each additional dose. Therapy should be discontinued when shortening fraction < 20% and percent of predicted shortening velocity < 50%. However, selected patients with satisfactory LV performance who have received dosages of 500 mg/m² may be considered for continued chemotherapy.     

Single institution experience with high-dose cyclophosphamide,continuous infusion vincristine,escalating doses of VP-16-213, and total body irradiation with unpurged bone marrow rescue in children with neuroblastoma

Seven consecutive autologous bone marrow transplants were performed in children with neuroblastoma with very good partial remission (VGPR). A combination of cyclophosphamide, escalating doses of VP-16-213, continuous infusion vincristine, and total body irradiation followed by infusion with unpurged bone marrow was used. The dose-limiting toxicity in this regimen was mucositis which occurred when the total dose of VP-16-213 was 2,400 mg/m². The response rate to this regimen was 4/7 (-CR 48+, 21+, 21+, 35+ mo) 3/7 had a CR/PR post transplant with progressive disease between 1 and 4 months later (mean 2.6 mo). We conclude that this regimen is well tolerated when the maximum dose of VP-16-213 does not exceed 1,800 mg/m². Further evaluation will be necessary with this regimen to determine its therapeutic value in a larger number of patients with neuroblastoma.     

Salvage chemotherapy for lymphoma with VP-16, ifosfamide,and cisplatin

Between 1983 and 1985, we conducted a phase II clinical trial using VP-16, ifosfamide, and cisplatin (VIP) in patients with refractory lymphoma. Twenty-eight patients with bidimensional measurable disease were treated with VP-16 (75 mg/m²), ifosfamide (1.2 g/m²), and cisplatin (20 mg/m²) as daily intravenous infusions for 5 consecutive days. N-Acetyl-cystein, 2 g orally every 6 h, was given as a uroepithelial protective agent. All patients had received extensive combination chemotherapy prior to beginning VIP (median number of regimens = 2). Of the 25 patients evaluable for response, 2 patients achieved complete remission and 7 achieved partial remission for an overall objective response rate of 36%. The length of responses ranged from 2 months to 13 months. The predominant toxicity of VIP was myelosuppression. Of 23 patients receiving more than one course of VIP, 17 (73%) had dose reductions or delays related to poor hematologic tolerance of therapy. Uroepithelial and renal toxicity were mild. VIP demonstrates therapeutic activity in refractory lymphoma and appears comparable to other ifosfamide/VP-16 based salvage regimens.     

Vindesine: A phase II study in childhood malignancies-A report for cancer and leukemia group B

Vindesine, a semisynthetic derivative of vinblastine sulfate, was tested for anti-tumor activity and clinical toxicity in 36 children. The drug was administered to the initial 13 patients entered into the study a 2 mg/m²/day for five days by IV bolus. Because of severe neurotoxicity and life-threatening gastrointestinal toxicity, the regimen in 23 patients was modified to 4 mg/m² IV infusion over four hours, weekly. This latter regimen was well tolerated, with acceptable gastrointestinal, hematological, and neurotoxicity. One child with acute lymphocytic leukemia resistant to vincristine had a transient Ml remission bone marrow. Improvement or stable disease was noted in one patient each with Ewing's sarcoma, neuroblastoma, and Hodgkin's disease.     

Dose escalation trial of cyclophosphamide with sargramostim in the treatment of central nervous system (CNS) neoplasms

We conducted a dose escalation trial of cyclophosphamide plus Sargramostim in the therapy of patients with newly diagnosed or recurrent central nervous system tumors. Cyclophosphamide was administered at doses ranging between 1.0 and 2.5 g/m² daily for two doses. Sargramostim was administered at a fixed dose of 250 μg/m² subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the absolute neutrophil count (ANC) was >1,000 cells/μl for two consecutive days. The MTD for patients who had not received any prior chemotherapy and who had received either no radiotherapy or radiotherapy confined to the cranium was 2.0 g/m² daily for two doses. The MTD for patients previously treated with chemotherapy or neuraxis radiotherapy was also 2.0 g/m² daily for two doses. Responses were seen in patients with medulloblastoma (8/9), glioblastoma multiforme (2/13), germinoma (1/1), and pineoblastoma (1/2). © 1995 Wi1ey-Liss Inc.     

COMPARISON OF DOXORUBICIN CARDIOTOXICITY IN PEDIATRIC SARCOMA PATIENTS WHEN GIVEN WITH DEXRAZOXANE VERSUS AS CONTINUOUS INFUSION

Doxorubicin is an effective agent for many malignancies. To limit cardiotoxicity, doxorubicin can be given as prolonged infusion (PIDX) or bolus infusion following dexrazoxane (DZX). The authors report their institutional experience comparing PIDX and DZX in a sarcoma cohort. Retrospective record review for newly diagnosed sarcoma patients at the University of Texas M.D. Anderson Cancer Center from June 1998 to June 2006. There were 23 Ewing's sarcoma (EWS) patients treated with DZX and 40 osteosarcoma (OS) patients treated with PIDX. The DZX group had higher mean cumulative anthracycline dose (510 mg/m² [SD 120 mg/m²] versus 414 mg/m² [SD 99 mg/m²], P = .002), however mean lowest left ventricular ejection fraction (EF) values were higher for DZX (52.5% [SD 5.6%] versus 47.2% [SD 10.9%], P = .014). Fifteen of 19 patients with cardiac dysfunction were PIDX patients (P = .15). Five PIDX patients required cardiac medication, and 1 patient died of congestive heart failure (CHF). Sixteen patients with cardiac dysfunction had improvement, demonstrated by EF ≥ 50% at last echocardiogram. Although not statistically significant, there were 4 DZX patients with cardiac dysfunction. Prospective studies are required to determine which strategy has long-term advantages and if certain patients are at increased risk for cardiac dysfunction.