Multiple causes of cerebrovascular events in children with tumors of the parasellar region.

Cerebrovascular arterial occlusion is a rare but devastating event causing long-term morbidity in children with tumors in the parasellar region. While usually associated with radiation therapy, there are a variety of host, tumor and treatment factors which predispose patients to significant vasculopathy. Case reports of 5 patients from St. Jude Children's Research Hospital with tumors in the parasellar region who presented with or developed vascular occlusive disease are summarized. Multiple factors are identified in these cases which probably impacted on the development of cerebral arterial occlusion with or without moyamoya syndrome. These include, but are not limited to, neurofibromatosis, tumor encasement of major cerebral vessels, surgical alterations, and radiation therapy. The literature supports multiple, potentially interactive etiologies for the development of vascular events in these patients, suggesting that their development is not simply a phenomenon related to radiation therapy.

Current therapy and new perspectives in the treatment of medulloblastoma.

Medulloblastoma, a malignant tumor arising from the medullary velum, is the most common malignant brain tumor of childhood. Local extension into the cerebellar hemisphere, infiltration of the floor of the fourth ventricle, and seeding into the subarachnoid space are common. Early diagnosis and improved treatment consisting of surgery followed by radiation and chemotherapy for selected high-risk patients has contributed to a dramatic change in survival. This article reviews current treatment strategies and describes new therapies that have the potential to improve the outlook of children with medulloblastoma.

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors.

PURPOSE: We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS: Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS: Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION: The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

A phase II study of every other day high-dose ifosfamide in pediatric brain tumors: a Pediatric Oncology Group Study.

Despite reported activity in many other solid tumors, high-dose ifosfamide produces few objective responses in recurrent pediatric brain tumors. Alkylating agents such as cyclophosphamide (CYCLO) possess good activity in many of solid tumors, including brain tumors. Although Ifosfamide (IFOS), a structural congener of CYCLO, has been suggested to have greater activity in several tumors, its activity in brain tumors is uncertain. We conducted a phase II trial of every-other day IFOS (3 gm/M2/qod x 3) in 87 recurrent pediatric brain tumors. Responses were evaluable in 71 patients. Partial responses occurred in 1/6 patients with low grade astrocytoma, 1/16 with malignant glioma, 1/16 with medulloblastoma, 1/3 with pineoblastoma and 1/12 patients with ependymoma. No responses occurred among 10 patients with brain stem gliomas or 8 patients with other brain tumors. Despite the poor objective response rate, 23/71 patients were clinically and imaging stable for periods of 8-62 weeks. There was no relationship between prior CYCLO treatment and subsequent response or failure with IFOS. The predominant toxicity was myelosuppression. Although generally reversible, prolonged suppression and sepsis were responsible for the deaths of 3 heavily pretreated patients. Renal toxicity was uncommon; 2 patients had grade III, and one grade IV renal tubular dysfunction. One patient had grade IV hematuria. Neurotoxicity was less common than in studies of daily ifosfamide; only 1 patient had grade IV neurotoxicity. Three patients had grade III or IV IFOS related hyponatremia. Despite the good stable disease rate, the poor rate of objective response suggests that IFOS monotherapy possesses little clinically meaningful activity in brain tumors.

Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy.

PURPOSE: To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS: Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS: Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION: Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

Hyperfractionated irradiation and concurrent cisplatin in brain stem tumors: a Pediatric Oncology Group pilot study (9139).

A phase I Pediatric Oncology Group Study was performed combining 7,020 cGy hyperfractionated irradiation (117 cGy twice daily separated by 6 h) with increasing concurrent doses of cisplatin given with the intent of radiosensitization as treatment for children with newly diagnosed brain stem tumors. Cisplatin was infused over 120 h on weeks 1, 3, and 5 during a 6-week radiotherapy course. The following cisplatin dose levels were studied: (1) 50 mg/m2/120 h, (2) 75 mg/m2/120 h and (3) 100 mg/m2/120 h. Sixteen of 17 children completed therapy. One child expired after 2 days of treatment secondary to massive intratumoral hemorrhage. At cisplatin dose level 3 (100 mg/m2/120 h), grade 2-4 myelosuppression was encountered in 3 of 5 evaluable patients. Otherwise, no other excessive toxicities, including renal and ototoxicity, were noted.

Quality of survival among children treated for brain stem glioma.

In order to describe the status of long-term survivors of brain stem glioma, neuropsychological and behavioral measures were obtained a median of 2.5 (range 1.5-5.6) years after diagnosis from 16 survivors of 51 consecutively diagnosed children with brain stem glioma between 1983 and 1991. Among 11 children with dorsally exophytic tumors, 7 were treated with surgery alone (SRG) and 4 received conventionally fractionated local cranial radiation therapy (CFRT; 54-56 Gy) to the brain stem following surgery, 3 of these because of recurrent disease. Five others with diffusely infiltrative brain stem tumors received hyperfractionated radiation therapy (HFRT; 70.2 Gy) to the brain stem; 4 following biopsy or limited resection and 1 without prior surgery. IQs of children in the CFRT (mean 89, SD 24.4) and HFRT (mean 85, SD 12.7) groups were not significantly different. Children in the SRG group had significantly higher IQs (mean 100, SD 11.0) and fewer neurologic deficits than those who had received CFRT or HFRT. However, after statistically controlling for severity of neurologic deficits, treatment had no effect on IQ. The severity of residual neurologic deficits accounted for 42% of the variance in IQ scores; children with fewer neurologic problems scored higher. Additional studies are required to evaluate the potential neuropsychological benefits of equivalent total doses of HFRT compared to CFRT.

Peritoneal metastases in two patients with pineoblastoma and ventriculo-peritoneal shunts.

We report the uncommon occurrence of ventriculo-peritoneal shunt-associated peritoneal metastases in two patients with pineoblastoma. In one patient, the peritoneal cavity was the only site of recurrence; there was no evidence of disease recurrence in the central nervous system. One other patient with recurrent intracranial disease had synchronous, but asymptomatic, peritoneal metastases which were detected on an elective ultrasound. Although rare, peritoneal metastases appear to respond well to systemic chemotherapy. Ultrasound surveillance of the abdomen should be considered as a part of the routine follow-up evaluation in patients with embryonal central nervous system tumors and ventriculo-peritoneal shunts.

Predominance of pilocytic histology in dorsally exophytic brain stem tumors.

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

Relation of tumor-cell ploidy to survival in children with medulloblastoma.

PURPOSE: To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS: Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS: Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION: This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas.

PURPOSE: Evaluation of high-dose chemotherapy with autologous bone marrow rescue (ABMR) in pediatric malignant gliomas. PATIENTS AND METHODS: Newly diagnosed (n = 11) and recurrent (n = 2) malignant glioma patients received high-dose chemotherapy within 4 weeks of surgery; three had near total and 10 had subtotal resection/biopsy. High-dose thiotepa (300 mg/m2) and cyclophosphamide (2 g/m2) daily for 3 days were followed by ABMR; response was evaluated at day 30. At day 60, patients with at least stable disease received hyperfractionated (n = 9) or conventional external-beam radiotherapy (n = 2) preceded by local radioactive iodine 125 implantation (n = 2) or radiosurgery (n = 1). RESULTS: Grade III and IV toxicities after ABMR consisted of mucositis (n = 12), cardiomyopathy (n = 1), acute abdomen (n = 1), pneumonitis (n = 2), and infection (n = 2). One complete and three partial responses were observed; the objective response rate was 31% (95% confidence interval, 9% to 61%). Seven had stable disease, one had disease progression, and one died of toxicity before response evaluation. The median overall and progression-free survival durations after combined modality therapy were 14 months (range, 4 to 30+) and 9 months (range, 0 to 30+), respectively. One patient remains progression-free at 30+ months. Radionecrosis and white matter changes occurred in three patients: one after hyperfractionated irradiation, and two after 125I implants. CONCLUSION: For patients with bulky residual disease after surgery, survival with this aggressive chemotherapy and radiation regimen is not better than that reported for conventional treatment regimens.

A phase II evaluation of thiotepa in pediatric central nervous system malignancies.

BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.

A phase I study of ifosfamide given on alternate days to treat children with brain tumors.

BACKGROUND: Ifosfamide with Mesna, given every other day over a 5-day period, was evaluated in 20 children with recurrent or progressive primary brain tumors. METHODS: The patients were assigned to dosage cohorts separated on the basis of prior exposure to cisplatin (n = 10) or the absence of such exposure (n = 10). The initial dose in each treatment arm was 2133 mg/m2 every other day for three doses, which represented 80% of the total dose delivered in our prior study of ifosfamide given daily over 5 days. The dose was escalated by 20% in each of the two subsequent cohorts (2560 mg/m2 and 3072 mg/m2 every other day for three doses). RESULTS: The hematologic toxicity was dose limiting. Prior exposure to cisplatin did not seem to increase the hematologic toxicity. The most frequent and significant metabolic disturbance was hyponatremia, resulting in self-limited seizure activity in three patients. This complication was prevented in subsequent patients by changing the post-ifosfamide hydration fluids from 5% dextrose in quarter normal saline to 5% dextrose in normal saline. CONCLUSIONS: Although no child achieved a complete response, the activity of ifosfamide was demonstrated for a variety of tumors. The recommended dose of ifosfamide in a Phase II study for brain tumors is 3000 mg/m2 given with Mesna every other day for three doses.

Response of pediatric low grade gliomas to chemotherapy.

Thirteen patients with low grade astrocytomas were treated with alkylating agent or platinum-based chemotherapy regimens. Eleven of these patients received chemotherapy as their initial postoperative treatment modality, and 2 others as treatment for progressive disease postradiation therapy. Responses were objectively determined using CT or MRI. One patient had a complete response (CR), 6 had partial responses (PR), and 3 others had stable disease (SD) as their best response. Clinical responses paralleled those determined objectively. Chemotherapy was well tolerated with the exception of ototoxicity in 4 patients treated with cisplatin. Despite good initial responses, 5 of 6 patients who received no further treatment postchemotherapy (4 PR, 1 SD) developed progressive disease 5-13 months after completing chemotherapy. The remaining 4 patients with objective responses or stable disease (1 CR, 2 PR, 1 SD), all received further postchemotherapy treatment with radiation therapy or surgery, and have not demonstrated disease progression. Our experience suggests that alkylator or platinum-based chemotherapy can successfully delay the growth of these locally infiltrative neoplasms, and should be considered in their primary management. Despite the experience of others, further therapy appears necessary in patients with residual CT or MRI abnormalities postchemotherapy.

Neuraxis dissemination in pediatric brain tumors. Response to preirradiation chemotherapy.

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal metastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression.

Primary extracranial neuroblastoma with central nervous system metastases characterization by clinicopathologic findings and neuroimaging.

The authors report the clinicopathologic and neuroimaging findings in ten children with primary abdominal or thoracic neuroblastoma who relapsed in the central nervous system (CNS) without evidence of concurrent intracranial extension from adjacent bone, dura, or dural sinus metastases. At diagnosis, the patients ranged in age from 0.3 to 4.5 years (median, 2 years). Their times to CNS relapse ranged from 2 to 34 months from diagnosis. In seven patients the relapse occurred from 1 to 14 months after elective discontinuation of therapy. In four patients, the CNS relapse was the primary (isolated) adverse event. Four patients could not be treated at the time of relapse, and they died within 7 days of progressive CNS disease. In the remaining group, craniospinal irradiation with or without administration of a platinum compound and an epipodophyllotoxin caused complete CNS remissions lasting 4, 5, 16, and 62+ months. Neuroimaging and autopsy findings indicated that cerebrospinal fluid is the major pathway for neuraxis dissemination by neuroblastoma cells. There was no evidence of dural penetration in any patient. The possibility of relapse in the neuraxis should be considered for any patient with neuroblastoma who had neurologic deterioration. A combination of craniospinal radiation and administration of a platinum compound and an epipodophyllotoxin will induce complete responses in some patients with neuraxis involvement by neuroblastoma, but the risk of subsequent failure outside the CNS remains high.

High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease.

Although long-term transfusion therapy is at least 90% effective in preventing recurrent strokes after an initial cerebrovascular accident in patients with sickle cell disease, it is unknown how long transfusion therapy should be continued. To address this question, we prospectively discontinued transfusions in 10 patients with sickle cell disease whose median duration of transfusion therapy after an initial stroke was 9 1/2 years (range 5 to 12 years). Before the transfusions were discontinued, patients were examined by cerebral angiography, magnetic resonance imaging of the head, neuropsychologic testing, electroencephalography, and a complete neurologic examination. Within 12 months after transfusion therapy was stopped, 5 of 10 patients had had an ischemic event. Three events caused relatively mild deficits in the same areas as those originally affected. Two were associated with massive intracranial hemorrhage, including one on the contralateral side of original involvement. An additional patient died suddenly of unknown causes. Of the four remaining patients, three declined to resume transfusion and are relatively well at greater than or equal to 18 months after therapy was stopped. The studies performed before transfusions were stopped were not predictive of recurrent stroke. The risk of recurrent cerebrovascular accident in this group was significantly greater than the estimated risk of 10% in patients who are receiving long-term transfusion therapy (p = 0.002). This adverse outcome suggests that patients with sickle cell disease who have had a stroke must receive long-term transfusion indefinitely or a suitable therapeutic alternative must be devised.

Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: a phase II study.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy.

In an effort to reduce the severity of late neurotoxicities associated with cranial irradiation, 14 infants and young children with malignant brain tumors were given preirradiation chemotherapy for 2 to 22 months (median, 8 months). Prospective neurodevelopmental evaluations were routinely conducted and now extend from 35 to 60 months (median, 41 months) postdiagnosis, and 10 to 52 months (median, 31 months) postirradiation in the 12 surviving children. At the initiation of chemotherapy, less than one fourth of the patients displayed normal performance status or mental functioning on age-corrected tests; the majority remained stable or declined while receiving chemotherapy. Declining mental development and adaptive behavior were noted in six patients following radiation therapy with only two patients now functioning in the normal range for age. The analysis suggests that neurodevelopmental progress is a function of multiple factors, including neurologic and sensorimotor deficits associated with the tumor, surgical intervention, and chemotherapy that antedated radiation therapy. This implies that delaying irradiation will not necessarily improve the patients' functional status. Whether the interval of postponement of irradiation evidenced in this sample will translate into an ultimately better quality of life remains unknown. Given the probable interaction of multiple risk factors, well-controlled prospective clinical trials are needed to definitively analyze this issue.