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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1894-1901 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.075 Age Is a Risk Factor for Chemotherapy-Induced Hepatopathy With Vincristine, Dactinomycin, and CyclophosphamideFrom the Mayo Clinic, Rochester, MN; Children's Hospital and Regional Medical Center, Seattle, WA; University of Nebraska Medical Center, Omaha, NE; Duke University Medical Center, Durham, NC; Children's Hospital of Philadelphia, Philadelphia, PA; University of Oklahoma Health Sciences Center, Oklahoma City, OK; and Soft Tissue Sarcoma Committee of the Children's Oncology Group, Arcadia, CA. Address reprint requests to Carola A.S. Arndt, MD, Department of Pediatric Hematology/Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: carndt{at}mayo.edu
PURPOSE: To evaluate the spectrum of and determine the risk factors for the development of liver toxicity (hepatopathy) after therapy with vincristine, dactinomycin, and cyclophosphamide (VAC) for rhabdomyosarcoma in children and adolescents. PATIENTS AND METHODS: We prospectively captured all events of hepatopathy occurring on the ongoing Children's Oncology Group intermediate risk protocol, D9803, for children with rhabdomyosarcoma. Patients enrolled onto this trial were randomly assigned to receive either VAC alone or VAC alternating with vincristine, topotecan, and cyclophosphamide. In addition, we reviewed the toxicity database and requested additional information for all patients with elevated bilirubin or transaminase levels. Risk factors were analyzed. RESULTS: Of 339 patients enrolled through August 2002, 18 developed hepatopathy. All events were captured by mandated toxicity reporting and filing of MedWatch forms, with no additional cases found after the additional search of the database. Four children died after developing this toxicity. All cases occurred after cycles of VAC (n = 16) or vincristine and cyclophosphamide with concomitant abdominal radiotherapy (n = 2). The onset of hepatopathy was 5 to 16 days from the start of a treatment cycle. For the 89 patients under 36 months of age, the risk of hepatopathy was 15%, with two deaths. For the 239 children 3 years of age or older, the risk for hepatopathy was 4%, with two deaths. CONCLUSION: The greatest risk factor for development of hepatopathy after VAC therapy was age. Dose modifications for younger children receiving VAC therapy are recommended.
Dose-intensive therapy for malignancy may result in hepatic injury. Hepatic veno-occlusive disease (HVOD) is a well-known complication of some conditioning regimens used for stem-cell transplantation.1,2 This complication has been associated with regimens using total-body irradiation and cyclophosphamide. HVOD has also been observed in patients with acute lymphoblastic leukemia receiving 6-thioguanine.3 Over the past two decades, HVOD has been increasingly recognized as a complication of conventional chemotherapy with or without abdominal irradiation, which most frequently occurs in children with Wilms' tumors treated with dactinomycin.4-8 These reports suggest that the dose rate for dactinomycin may be an important risk factor for hepatic toxicity. In addition to HVOD, many other terms have been used to describe this condition, including hepatopathy thrombocytopenia syndrome (HTS),8 severe hepatic toxicity, and, most recently, sinusoidal obstruction syndrome.9 Chemotherapy-induced hepatopathy may represent a spectrum of toxic insult to the liver, with only a minority of cases resulting in severe HVOD. For this reason, we refer to the spectrum of liver toxicity seen in association with vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy occurring in children with rhabdomyosarcoma as hepatopathy. Although hepatopathy was reported with the use of dactinomycin in the 1970s, there was little recognition of this risk for children with rhabdomyosarcoma until the case report of Kanwar et al.7 Ortega et al4 reported the occurrence of hepatopathy on the Intergroup Rhabdomyosarcoma Study Group (IRSG)-IV (1991–1997), with most cases developing after VAC chemotherapy. The IRSG-IV chemotherapy doses were dactinomycin 0.015 mg/kg/d for 5 days and cyclophosphamide 2.2 g/m2 for 1 day, with 50% dose reductions for infants less than 1 year old. Six cases of HVOD were reported on the VAC-only arm, for an incidence of 3.1% on that regimen.4 We updated this analysis of hepatopathy on IRSG-IV, finding 13 cases of hepatopathy (4.5%) among 292 patients who received the standard VAC regimen. For patients younger than 3 years, the incidence was 7% (six of 84 patients), and for patients older than 3 years, it was 3.4% (seven of 206 patients). There was one death that was possibly attributable to hepatopathy among these 13 cases. Hepatopathy was not found to be prognostic for failure-free survival (P. Breitfeld, personal communication, October 2003). In September 1999, the IRSG (subsequently merged into the Children's Oncology Group) began D9803, a randomized study of VAC versus VAC alternating with vincristine, topotecan, and cyclophosphamide (VTC) for patients with intermediate-risk rhabdomyosarcoma. Because of report by Ortega et al,4 we prospectively monitored this study for the development of hepatopathy. Accrual to D9803 was temporarily suspended in August 2002 after 18 cases of HVOD occurred, four of which were fatal. This report describes the hepatopathy syndrome seen in patients enrolled onto D9803, analyzes risk factors for hepatopathy, and discusses the rationale for changes in drug dosing as a result of the analysis.
Protocol D9803 opened to patient entry on September 1, 1999. Eligibility for study entry included patients less than 21 years of age with rhabdomyosarcoma at intermediate risk of treatment failure determined by assessment of extent of disease, tumor histology, and age. Patients enrolled onto D9803 were randomly allocated to the control VAC arm or an experimental arm alternating the same doses of VAC chemotherapy with cycles of VTC, except for patients requiring immediate radiation therapy who were nonrandomly treated with VAC therapy. Cycles of VAC and VTC were delivered every 21 days, with weekly vincristine during weeks 0 to 11, 18 to 24, and 30 to 36. The planned duration of therapy was 42 weeks. Doses of VAC (when given with dactinomycin) changed over the course of study and are listed in Table 1, with the schedule for drug administration detailed in Fig 1. The schedule of administration for dactinomycin was changed from the IRSG-IV schedule of five doses per week (mg/kg dosing) to a single dose (mg/m2 dosing), a schedule previously reported to be safe,10 for patient convenience and to decrease days in the hospital. However, the initial protocol version dosed all children under 3 years of age on a mg/kg basis because of the high surface area to weight ratio in infants and young children (Fig 2). Doses for the 1- to 3-year age group were determined by dividing the mg/m2 dosing by 30. Doses in children less than 1 year old were halved because previous IRSG experience noted marked increases in chemotherapy toxicity in infants, and IRSG-IV dosed infants at 50% of the doses provided for older children.
In an amendment activated on February 21, 2000, doses of vincristine and cyclophosphamide for infants under 1 year old were changed to 50% of the dose prescribed by body-surface area (BSA), with dose escalation as tolerated. The dose of dactinomycin was 0.025 mg/kg (50% of the prescribed dose converted to a per kilogram dose). This amendment of changing the vincristine and cyclophosphamide dosing was intended to avoid a double dose reduction for infants, a group recognized to be at higher risk for treatment failure,11,12 but it kept the dose modification of dactinomycin for infants under 1 year the same to be consistent with the IRSG-IV dose reduction guidelines, as well as to provide consistency across rhabdomyosarcoma studies. For the same reason of consistency across rhabdomyosarcoma studies, the dose calculation for VAC was changed from weight to BSA for patients 1 to 3 years old and/or less than 0.6 m2. Other open rhabdomyosarcoma studies at the time had no modification for the subset of patients who were 1 to 3 years old and/or less than 0.6 m2. After the observation of 18 cases of hepatopathy and four deaths (more toxicity than what had been anticipated for this dose of VAC therapy), the protocol accrual was temporarily suspended in August 2002. The study reopened in December 2002, with additional dosing modifications based on the analysis described here. Anticipating that hepatopathy would occur, the study was prospectively monitored for hepatopathy from its inception, defining HVOD as pathologic confirmation by liver biopsy or reversal of portal venous flow by ultrasound or two or more of the following: bilirubin more than 1.4 mg/dL, unexplained weight gain greater than 10% of baseline weight or ascites, and hepatomegaly or right upper quadrant pain without other explanation. HVOD was graded as mild, moderate, or severe, using the definitions listed in Table 2.
Notification of the study chair and filing of a MedWatch form for any case of HVOD were required. Both the study committee and the data monitoring committee monitored the incidence of hepatopathy throughout the study. In addition, for this report and to ensure complete case ascertainment, the toxicity database for the D9803 study was searched for any patients who had elevated grade 3 or greater transaminases, grade 2 or greater hyperbilirubinemia or abnormal portal vein flow, grade 1 or greater nonmalignant ascites, hepatic enlargement, weight gain, bone marrow transplantation complex/multicomponent, or hepatic pain. Any suspected case identified with a suspicious toxicity triggered a veno-occlusive disease (VOD) questionnaire form, which was sent to the treating physician requesting clinical data and outcome. This study was activated by the IRSG, and subsequently, the Soft Tissue Sarcoma Committee of the Children's Oncology Group assumed responsibility for its conduct. Approval of the protocol and an informed consent statement was obtained by each participating institution's local institutional review board, in accordance with established policies. Informed consent for study enrollment was obtained from each subject or their guardian.
Statistical Considerations
Protocol Monitoring By June 30, 2002, 16 cases of HVOD or hepatic dysfunction (hepatopathy) had been reported on D9803 among 328 patients, with three deaths. An additional nonfatal case that occurred before July 2002 was reported later. One additional death was reported in August 2002. Although not meeting the established monitoring rule guideline, study accrual was suspended pending further evaluation of this toxicity. In addition, accrual was suspended to D9602 and D9802, the Children's Oncology Group companion studies for low- and high-risk rhabdomyosarcoma using the same VAC dosing schedule. All cases of VOD were identified by the study's toxicity forms or MedWatch reports. No additional cases of VOD or hepatopathy were identified from VOD forms sent to physicians caring for patients with suspicious toxicity.
Characteristics of the patients on D9803 who developed hepatopathy or HVOD are listed in Table 3. Compared with study patients who did not develop hepatopathy, patients with HVOD were younger and had a higher incidence of pelvic sites. The estimated cumulative incidence of hepatopathy for all 339 eligible patients enrolled through August 2002 was 6%. In patients aged 0 to 35 months, the incidence of hepatopathy was 14%, and in patients aged 36 months or more, it was 4% (P = .003; Fig 3). The incidence of hepatopathy for patients aged 36 months or more treated on D9803 (4%) was no different from that seen on the previous IRSG-IV trial (3%, P = .74). The estimated rate of hepatopathy in the younger age group seen on D9803 (14%) was higher than that seen for similar patients on IRSG-IV (7%), although the difference did not reach statistical significance (P = .16) perhaps because of the small numbers of patients in these subsets. The incidence of death from VOD was also higher in the younger patients (two of 93 patients aged 0–35 months, 2.2%; and two of 246 patients aged 36 months or older, 0.8%).
Characteristics of hepatopathy are listed in Table 4. No cases of hepatopathy occurred after VTC chemotherapy. The cumulative incidence of hepatopathy was similar on the two treatment regimens (6% for patients assigned to VAC, and 7% for patients assigned to VAC-VTC; P = .82).
The median time from the last VAC or vincristine and cyclophosphamide chemotherapy cycle to presentation with hepatopathy was 9 days (range, 5 to 16 days). The majority of patients (15 of 18 patients) developed hepatopathy within the first 12 weeks of therapy (one patient after week 0 VAC, three after week 3 VAC, eight after week 6 VAC, and two after week 9 VAC, and one patient had elevated liver enzymes after weeks 0 and 6). The one patient who developed hepatopathy after week 0 was a 3-month-old who received full per kilogram dosing of dactinomycin and cyclophosphamide, rather than the 50% dose modification in the protocol. One of the 18 patients was found to have hepatopathy at the time of second-look surgery when incidental liver biopsy was performed. In retrospect, this patient had had elevated transaminases after week 0 and week 6 VAC. Two patients developed hepatopathy after receiving vincristine and cyclophosphamide only, after weeks 15 and 18, while receiving concomitant abdominal radiotherapy. The only patient to develop hepatopathy after VAC later than week 9 was a child who had received full-dose therapy based on BSA for the first time at week 18 after her first birthday. This patient also received two additional doses of dactinomycin at weeks 15 and 18 not specified by protocol because of parental refusal of radiation therapy. Characteristics of the hepatopathy were highly variable. Eight of 16 patients who had hepatic ultrasound examinations had reversal of or decreased flow in portal veins. Five patients had bilirubin values of less than 2 mg/dL, and five patients had bilirubin values over 15 mg/dL. Transaminase (ALT or AST) levels ranged from 346 to 31,000 U/L. All but three patients had ascites; two patients had relatively small elevations in transaminases and bilirubin, but the third patient had severe and fatal liver disease. Four patients died after developing VOD; three had serum bilirubin over 15 mg/dL. Ten patients recovered completely, with no subsequent elevation of transaminases or continued jaundice, coagulopathy, hepatic fibrosis, or portal hypertension. Three patients recovered with mild elevations of transaminases less than or equal to twice the normal range, and one patient continued to have enzyme elevation more than twice the normal range. Four patients continued with treatment on study, and 10 went off study. Of the patients who went off study, eight received therapy with vincristine, ifosfamide, and etoposide or ifosfamide and etoposide with one patient receiving two additional vincristine and cyclophosphamide courses at the end of therapy. Two patients received therapy with vincristine, ifosfamide, and etoposide, alternating with VTC. Of the four patients who continued on study, the patient in whom the hepatopathy was incidentally found continued receiving full-dose VAC therapy, and three others received additional VAC therapy with doses reduced and then gradually escalated to the newly modified doses. Of the 14 patients who recovered from hepatopathy, 13 patients are in continuous remission a median of 26 months (range, 7 to 40 months) after diagnosis of rhabdomyosarcoma, and one patient had a local recurrence 29 months after diagnosis.
HVOD is a well-described complication of bone marrow transplantation. Hepatopathy has also been reported after conventional-dose chemotherapy and is most frequently observed with the treatment of Wilms' tumor with dactinomycin. Our report expands on the association of hepatopathy seen in the treatment of rhabdomyosarcoma with dactinomycin and cyclophosphamide. Variable laboratory and clinical definitions of hepatopathy complicate the comparison of HVOD rates between tumor types and treatments.1,4-6, 8,15-18 Cooperative group trials of therapy for Wilms' tumor have demonstrated liver toxicity with dactinomycin, usually in a dose-dependent manner. On the International Society of Pediatric Oncology (SIOP)-9/German Pediatric Oncology Hematology group study, the incidence of severe hepatotoxicity (defined in accordance with the National Wilms' Tumor Study criteria as increase in transaminases to at least 10-fold over normal) was 10% when dactinomycin was given at a dose rate of 0.45 mg/m2/d or 15 µg/kg/d for 3 to 5 days or 30 µg/kg for 1 day. When increased hepatotoxicity was noted, dose calculations were adjusted to body weight rather than surface area. However, a subsequent analysis of the overall rate of preoperative hepatotoxicity showed no significant difference between children whose dose was calculated on the basis of BSA compared with those whose dose was calculated based on body weight. Within the subgroup of children weighing 12 kg or less, the incidence of hepatotoxicity was lower with dosing of dactinomycin by weight compared with by BSA. However, this difference was not statistically significant.15, 16 Severe HTS was seen in six of 355 patients treated on the United Kingdom Children's Cancer Study Group Wilms' Tumor Trials 1 and 2. The onset of HTS was less than 10 weeks after diagnosis in all patients. The dose of dactinomycin was 1.5 mg/m2, the same dose given on the current D9803 study after the first amendment to patients older than 1 year. None of these patients had received abdominal radiotherapy. The criteria for identifying HTS meant that only severe cases were detected, but the authors estimated that if milder cases had been included, the incidence would have been approximately 3%.8 National Wilms' Tumor Study-4 randomly compared single-dose dactinomycin (initially at 60 µg/kg, then decreased to 45 µg/kg) to divided-dose dactinomycin at 15 µg/kg/d for 5 days. In nonirradiated patients, the incidence of severe hepatic toxicity was 14.3% in patients treated with the 60 µg/kg single dose, 3.7% in patients treated with the 45 µg/kg single dose, and 2.8% in patients treated with 15 µg/kg/d for 5 days (P = .025).6 This indicates that total dactinomycin dose and fractionation of the dose are interacting variables in hepatopathy risk. Dosing interval and fractionation have been evaluated as alternative risk factors for dactinomycin-associated hepatopathy. In a letter to the editor of The Lancet, the Brazilian group concluded that there was no difference in the rate of hepatotoxicity when patients were treated with a divided-dose versus a single-dose regimen of dactinomycin. However, they postulated that the lower frequency (although not significant) observed on the single dose was the result of a longer interval between dactinomycin doses for patients on that regimen.19 However, on the D9803 study reported here, there was no difference in the rate of hepatopathy when dactinomycin was given every 3 weeks (VAC arm) versus every 6 weeks (VAC-VTC arm). In the same issue of The Lancet, in another letter, D'Angio20 concluded that dactinomycin given as a single dose of 45 µg/kg is as well tolerated as divided doses of 15 µg/kg/d for 5 days. He speculated that the increased incidence of hepatopathy on National Wilms' Tumor Study-4 compared with previous trials may be a result of heightened awareness of this complication. More limited data regarding the incidence of hepatopathy after dactinomycin therapy for rhabdomyosarcoma suggests that the risk of HVOD is similar to that seen with Wilms' therapy. Carli et al10 reported on toxicity after single high-dose versus standard 5-day divided-dose dactinomycin in childhood rhabdomyosarcoma. Seventy patients were randomly assigned to receive one of the following two chemotherapy regimens: vincristine, 1.5 mg/m2 intravenously (IV) days 1 and 8; cyclophosphamide, 275 mg/m2 IV days 1 through 5; and dactinomycin, 0.45 mg/m2 IV days 1 through 5 every 28 days for three cycles (33 patients), or cyclophosphamide, 150 mg/m2 intramuscularly days 1 through 7; vincristine, 2.0 mg/m2 IV day 8; and dactinomycin, 1.7 mg/m2 IV day 8 every 21 days for four cycles (37 patients). There was a low incidence of toxicity, and no increased toxicity was observed in patients treated with high, single-dose dactinomycin, although the numbers of the patients in the study were small, perhaps underestimating the true incidence of HVOD. High single-dose dactinomycin was felt to provide the advantage of patient convenience. The dose given as a pulse on this study was even higher (1.7 mg/m2) than on the current D9803 study. We have shown that the clinical picture of hepatopathy after VAC is a spectrum of disease ranging from mild hyperbilirubinemia and elevated transaminases with no other clinical findings to florid hepatic failure, reversal of flow in the portal venous system, and death. All cases in this series were associated with dactinomycin and cyclophosphamide therapy, with the exception of two cases associated with concurrent abdominal radiation while receiving vincristine and cyclophosphamide therapy. Often, the onset is heralded by severe thrombocytopenia refractory to platelet transfusion (data not shown) and may be confused with disseminated intravascular coagulation or sepsis, especially in the setting of febrile neutropenia; however, previous reports have indicated that thrombocytopenia without neutropenia may be one of the earliest signs of impending hepatopathy.21 The mainstay of care is supportive therapy and careful attention to fluid balance, although treatment with N-acetylcysteine, defibrotide and tissue plasminogen activator, heparin, and infusions of antithrombin III have all been used with variable results.1,2, 22 Most patients who survive an episode of hepatopathy recover completely. In one case in our series, liver biopsy showed VOD that had not been suspected clinically. Unique in our evaluation of hepatopathy during therapy for rhabdomyosarcoma was the identification of age as a risk factor for development of hepatopathy. Children under 3 years of age had a nearly four-fold greater incidence of hepatopathy compared with older children (15% v 4%, respectively). The greater incidence in children under 3 years of age may be a result of the fact that with the first amendment of the protocol D9803, many patients between 12 and 36 months received dactinomycin doses that were over 0.06 mg/kg (data not shown), a dose range that has been associated with a higher incidence on some, but not all, reports of hepatopathy. The ratio of BSA to weight falls sharply during the first year and then falls more gradually until it reaches adult values by approximately 16 years. It is still quite high from age 1 to 3, thus perhaps rendering such patients more susceptible to the toxic effects of chemotherapy if they are dosed according to BSA. The guidelines for dosing babies and younger children are not uniform in cooperative-group protocols, and this experience suggests development of standardized guidelines for dosing younger children. Joshi et al11 and Ferrari et al12 reported that younger children with rhabdomyosarcoma have a worse outcome overall. Ferrari et al reported that the 5-year event-free survival rate for infants under 1 year of age was only 42.3% compared with the event-free survival rate for all patients treated on IRSG-IV of 77% at 3 years.23 The reasons for this may result from the higher incidence of protocol deviations, unwillingness to irradiate small children, or different tumor biology as a result of some as yet unidentified biologic factor in this age group. Thus, one is reluctant to recommend too aggressive dose modifications for this group of high-risk patients. The risk of life-threatening toxicity must be weighed against the risk of disease recurrence and poor salvage rate in heavily pretreated patients.24 Determining the exact cause for the observed hepatopathy on D9803 is complex. We anticipated that some children enrolled onto D9803 would develop liver dysfunction, given our experience with the previous study, IRSG-IV4 Both trials used the same high doses of cyclophosphamide that have been implicated in causing hepatopathy. Although much of the experience with Wilms' tumor therapy suggests that dosing of dactinomycin on the basis of BSA provides relatively large per kilogram doses to younger children, the United Kingdom Children’s Cancer Study Group (UKCCSG) Wilms’ tumor trials 1 and 2 used dactinomycin doses of 1.5 mg/m2, with a 1.7% incidence of hepatopathy.25 Use of two hepatotoxic drugs, cyclophosphamide and dactinomycin, in combination on D9803 may have increased the risk of hepatopathy over the risk with either drug alone. On the basis of the analysis of the risk factors for development of hepatopathy on this study, the D9803 study committee instituted dose modifications that would most impact the group of patients at highest risk for this complication, children under 36 months. Dactinomycin is now dosed at 0.045 mg/kg for all patients, regardless of age, with additional 50% reduction for infants under 1 year of age. Vincristine is also dosed on a per kilogram basis for children under 36 months of age, at 0.05 mg/kg, to be consistent with the per kilogram dosing for cyclophosphamide and dactinomycin. Cyclophosphamide is dosed at 73 mg/kg for children under 36 months of age, with additional 50% dose reduction for babies under 1 year of age. At 36 months of age, both vincristine and cyclophosphamide are dosed on the basis of BSA (1.5 mg/m2 and 2.2 mg/m2, respectively). These modifications result in a dose reduction of approximately 25% in those patients at highest risk for hepatopathy. New monitoring rules have also been instituted that will ensure detection of a rate of hepatopathy above the expected rate of 3% to 4%. Awareness of this serious complication should also allow early institution of supportive care measures.
The authors indicated no potential conflicts of interest.
We thank Cynthia G. Miller for secretarial assistance in manuscript preparation.
Supported by grant Nos. U10 CA098543, U10 CA24507, and CA72989 from the National Cancer Institute, Bethesda, MD. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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17. Bearman S: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85:3005-3020, 1995 18. Bearman S: Avoiding hepatic veno-occlusive disease: What do we know and where are we going? Bone Marrow Transplant 27:1113-1120, 2001[CrossRef][Medline] 19. De Carmargo B: Hepatotoxicity and actinomycin D. Lancet 335:1290, 1990 20. D'Angio GJ: Hepatotoxicity and actinomycin D. Lancet 335:1290, 1990 21. D'Antiga L, Baker A, Pritchard J: Veno-occlusive disease with multi-organ involvement following actinomycin-D. Eur J Cancer 37:1141-1148, 2001
22. Kumar S, DeLeve L, Kamath P, et al: Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 78:589-598, 2003
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24. Pappo A, Anderson J, Crist W, et al: Survival After Relapse in Children and Adolescents with Rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17:3487-3493, 1999 25. Davidson A, Pritchard J: Actinomycin D, hepatic toxicity and Wilms' tumour: A mystery explained? Eur J Cancer 34:1145-1147, 1998 Submitted August 11, 2003; accepted February 27, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
