MYCN expression in neuroblastoma: A mixed message?
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Gene Amplification↗
Biomedical subjects
K K Matthay
Publications and source records attributed to K K Matthay.
Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular.
BACKGROUND: Ganglioneuroblastoma, nodular (GNBn) is a rare subtype of the family of neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) that are classified in the unfavorable histology group according to the International Neuroblastoma Pathology Classification (Shimada system). Tumors of this subtype have been considered to represent a prototypic example of biologically and clinically nonaggressive (Schwannian stroma-rich and stroma-dominant) components combined with biologically and clinically aggressive nodular (Schwannian stroma-poor) components. However, detailed histopathologic analysis as well as thorough prognostic evaluation of patients with this subtype has not been reported. METHODS: Pathology slides and reports from a total of 70 GNBn patients from the Children's Cancer Group (CCG)-3881 and CCG-3891 studies were reviewed. Sixty-eight tumors were classified in the favorable subset (FS) or the unfavorable subset (US) based on the evaluation of nodular components by applying the same histopathologic criteria (patient age, grade of neuroblastic differentiation, mitosis-karyorrhexis index) that are used for neuroblastomas in the International Neuroblastoma Pathology Classification. Patient prognosis as well as clinical and biologic characteristics within the subsets were analyzed, and the results were compared with those from 654 non-GNBn patients who were enrolled in the same CCG studies during the same period. RESULTS: Patients with GNBn tumors, usually diagnosed at age > 1 year, had a significantly lower overall 5-year event free survival (EFS) rate than patients with non-GNBn subtypes (44.7% EFS vs. 65.0% EFS; P = 0. 0073). A significant difference in the outcome of the patients between the FS (22 patients; 86.1% EFS; 95.0% survival rate) and the US (46 patients; 29.0% EFS; 40.7% survival rate) of the GNBn subtype (P < 0.0005) was shown. When the cohort of patients with GNBn tumors was subdivided into FS and US, the outcomes were similar to those of patients with tumors of favorable histology (397 patients; 90.5% EFS; 97.6% survival rate) and with tumors of unfavorable histology (257 patients; 27.0% EFS; 35.7% survival rate) of the non-GNBn type. The patients with US tumors frequently (63.0%) presented with distant metastasis. CONCLUSIONS: The current study demonstrates that the nodular components in GNBn tumors are not always aggressive. The prognosis of these patients can be determined by the analysis of age-linked histopathologic features.
Age Factors↗
Intraoperative radiation therapy for high-risk pediatric neuroblastoma.
PURPOSE: To evaluate the efficacy of intraoperative radiation therapy (IORT) in the treatment of high-risk pediatric neuroblastoma. METHODS AND MATERIALS: Between 1986 and 1998, 23 children received IORT for pediatric neuroblastoma. Electron beam energies ranged from 4 MeV to 16 MeV and median dose was 10 Gy (7-16 Gy). RESULTS: Twenty-one of 23 patients were classified as high-risk. A gross total resection (GTR) was achieved in 18 patients, of whom 6 experienced disease recurrence, 2 of which included a locoregional relapse as a component of failure. Fourteen of 18 patients receiving IORT after a GTR are disease-free survivors. A second subset of 5 patients had a subtotal resection (STR), with gross residual disease remaining after surgery. All 5 patients recurred locally, and all died of their disease. IORT was extremely well-tolerated in our cohort. Surgical resection and IORT resulted in the narrowing of the abdominal aorta and an atrophic kidney in 1 patient. CONCLUSIONS: For high-risk neuroblastoma patients, IORT as the only radiotherapy to the primary, produced excellent local control after a GTR. However, IORT as the sole radiotherapy to the primary was inadequate for patients with extensive adenopathy or an STR. In this setting, we are exploring the use of IORT as a boost in conjunction with external beam radiation therapy.
Adolescent↗
A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma.
BACKGROUND: Dose intensity is important in the response to chemotherapy in patients with advanced neuroblastoma. The aim of the current study was to determine the maximum tolerated dose of a combination chemotherapy regimen in the treatment of patients with recurrent neuroblastoma and peripheral neuroepithelioma (primitive neuroectodermal tumor [PNET]) and whether the use of growth factor would allow increased dose intensity. METHODS: Twenty-nine patients diagnosed with recurrent neuroblastoma or PNET were treated with a combination chemotherapy regimen of cisplatin, 160 mg/m(2)/96 hours; doxorubicin, 40 mg/m(2)/96 hours; and escalated doses of etoposide and ifosfamide. Granulocyte-macrophage-colony stimulating factor (GM-CSF) was administered beginning 24 hours after the completion of the chemotherapy. Courses were repeated at 28-day intervals. Once the maximum tolerated dose (MTD) was defined the interval between courses was shortened by administering the next course as soon as the patient's neutrophil and platelet counts had recovered to > 1500/microL and > 75,000/microL, respectively. RESULTS: Sixteen patients were treated at 3 dose levels. The MTD was defined as 10 g/m(2)/96 hours of ifosfamide and 800 mg/m(2)/96 hours of etoposide. Thirteen additional patients then were treated at 1 level below the MTD to try and decrease the interval between courses. A total of 12 of 29 patients developed a dose-limiting toxicity (DLT) after the first course of therapy. The most common DLT was gastrointestinal toxicity followed by hematologic toxicity. Twenty-seven patients developed standard National Cancer Institute criteria Grade 3 or 4 toxicity after the first course of treatment and 7 patients achieved a complete or partial response to the first course. The use of GM-CSF did not allow further dose intensification. CONCLUSIONS: This chemotherapy combination achieved a 31% overall response rate. A further increase in the dose intensity of this regimen may require supportive measures other than GM-CSF to decrease toxicity.
Adolescent↗
Multidrug resistance-associated protein 1 (MRP1) expression in neuroblastoma cell lines and primary tumors.
BACKGROUND AND PROCEDURE: MRP1 expression by neuroblastomas was evaluated by Northern blot analysis in 21 cell lines and 90 primary untreated tumors. Cytotoxicity assay in cell lines was performed for five anticancer drugs used in treating neuroblastoma. RESULTS: MRP1 expression did not correlate with drug resistance or with MYCN RNA expression in cell lines. MRP1 expression was higher in drug-sensitive cell lines established after chemotherapy relative to cell lines at diagnosis, but highly drug-resistant cell lines showed low MRP1 expression. Positive expression of MRP1 RNA in primary tumors was associated with a poorer survival relative to MRP1-negative tumors. However, MRP1 expression levels did not correlate with age, stage, MYCN amplification, or MYCN expression, and higher MRP1 expression was not associated with a worse outcome. CONCLUSIONS: In neuroblastoma, positive MRP1 RNA expression at diagnosis has prognostic significance, but high drug resistance is conferred by mechanisms other than MRP1.
ATP-Binding Cassette Transporters↗
Telomerase activity by TRAP assay and telomerase RNA (hTR) expression are predictive of outcome in neuroblastoma.
BACKGROUND: Recent studies have associated telomerase with prognostic factors and survival in neuroblastoma. PROCEDURE: We examined telomerase activity by telomere repeat amplification protocol (TRAP) and expression of the RNA component of telomerase (hTR) by Northern blotting in 106 primary neuroblastoma tumors and 22 established cell lines. RESULTS: Overall survival at 5 years for all 106 tumors was significantly better for patients with undetectable TRAP (75% vs. 59%; P = 0.03) or low hTR expression (84% vs. 43%; P < 0.0001), and especially for patients whose tumors had both low hTR expression and undetectable TRAP (all patients, 91% vs. 54%, P = 0.0002; for 17 stage IV-S tumors, 100% vs. 72%, P = 0.04). Strong expression of hTR was seen in 22 cell lines from aggressive tumors, and all maintained telomere length, but 3/22 were TRAP negative. CONCLUSIONS: These data suggest that both hTR expression and telomerase activity via the TRAP assay should be performed concurrently to predict survival in neuroblastoma patients, particularly in stage 4-S.
Child↗
Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors.
We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors.
Antineoplastic Agents↗
Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy.
IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.
Adolescent↗
Is there a role for retinoids to treat minimal residual disease in neuroblastoma?
A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered.
Humans↗
Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study.
PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group. PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children's Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features. RESULTS: EFS and OS (mean +/- SE) for all stage I patients were 93% +/- 3.0% and 99% +/- 1.0%, respectively, compared with 81% +/- 4.0% and 98% +/- 2. 0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P <.05). CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are >/= 2 years of age with either unfavorable histopathology or positive lymph nodes.
Adolescent↗
Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study.
PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy. PATIENTS AND METHODS: Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined. RESULTS: Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P =.005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age </= 3 months at diagnosis was significant for EFS (P =. 043), it was less significant for survival (P =.077). The only other significant factor predictive for improved survival was favorable Shimada histopathologic classification. Sites of metastatic involvement (liver, skin, or bone marrow) and surgical resection of the primary tumor were not significant for survival. CONCLUSION: This study confirms the favorable biologic features and excellent survival of infants with stage IV-S neuroblastoma with minimal therapy. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease may benefit from earlier and more intensive treatment.
Adrenal Gland Neoplasms↗
Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study.
PURPOSE: A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. PATIENTS AND METHODS: One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. RESULTS: The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. CONCLUSION: Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.
Biological Factors↗
Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children's Cancer Group study.
PURPOSE: To determine the independent prognostic significance of 1p36 loss of heterozygosity (LOH) in a representative group of neuroblastoma patients. PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered onto the most recent Children's Cancer Group phase III clinical trials were assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome band 1p36. Allelic status at 1p36 was correlated with other prognostic variables and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238 neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater than 1 year (P = .026), metastatic disease (P<.001), elevated serum ferritin level (P<.001), unfavorable histopathology (P<.001), and MYCN oncogene amplification (P<.001). LOH at 1p36 was associated with decreased event-free survival (EFS) and overall survival (OS) probabilities (P<.0001). For the 180 cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate regression model suggested a trend toward an independent association with decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore, allelic status at 1p36 was the only prognostic variable that was significantly associated with decreased EFS in low-risk neuroblastoma patients (P = .0148). CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful for predicting which neuroblastoma patients with otherwise favorable clinical and biologic features are more likely to have disease progression.
Child↗
Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group.
BACKGROUND: Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. METHODS: All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. RESULTS: The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027). CONCLUSIONS: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.
Adolescent↗
Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas.
Deletions of the long arm of chromosome 11 (11q) have been noted in primary neuroblastomas, but a comprehensive analysis has not been performed. Therefore, we analysed 331 neuroblastomas (295 sporadic, 15 familial and 21 tumor-derived cell lines) to determine the prevalence of 11q allelic deletions, to map the location of a putative tumor suppressor gene and to perform clinical correlative studies. Assays for loss of heterozygosity (LOH) were performed at 24 microsatellite loci spanning 11q. LOH was observed at multiple 11q loci in 129/295 (44%) sporadic neuroblastomas, 5/15 (33%) familial neuroblastomas, and 5/21 (24%) neuroblastoma cell lines. A single region of 2.1 cM within 11q23.3, flanked by markers D11S1340 and D11S1299, was deleted in all specimens with 11q LOH. Allelic loss at 11q23 was inversely related to MYCN amplification (P<0.001). Within the subset of cases with a single copy of MYCN, 11q LOH was associated with advanced stage disease (P=0.008), unfavorable histopathology (P=0.042), and decreased overall survival probability (P=0.008). However, 11q LOH was not independently prognostic in multivariate analyses. These data support the hypothesis that a tumor suppressor gene mapping within 11q23.3 is commonly inactivated during the malignant evolution of a large subset of neuroblastomas, especially those with unamplified MYCN.
Alleles↗
The International Neuroblastoma Pathology Classification (the Shimada system).
BACKGROUND: The International Neuroblastoma Pathology Committee, which is comprised of six member pathologists, was convened with the objective of proposing a prognostically significant and biologically relevant classification based on morphologic features of neuroblastic tumors (NTs) (i.e., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma). METHODS: A total of 227 cases were reviewed. Consensus diagnoses from morphologic features (criteria described separately) based on five of six or six of six agreements by the reviewer pathologists were used for prognostic analysis. Prognostic effects of morphology, both individual and in combination, taken in conjunction with age (Shimada classification, histologic grade, and risk group), were analyzed. RESULTS: Approximately 99% of cases (224 of 227) had consensus diagnoses for categorization: neuroblastoma (Schwannian stroma-poor), 190 cases; ganglioneuroblastoma, intermixed (Schwannian stroma-rich), 5 cases; ganglioneuroma (Schwannian stroma-dominant) maturing, 1 case; ganglioneuroblastoma, nodular (composite Schwannian stroma-rich/stroma-dominant and stroma-poor), 19 cases; and NT-unclassifiable, 9 cases. For the NTs, subtype (93% consensus: undifferentiated, 6 cases; poorly differentiated, 155 cases; and differentiated, 15 cases), mitosis-karyorrhexis index (90% consensus: low, 94 cases; intermediate, 40 cases; and high, 37 cases), mitotic rate (75% consensus: low, 89 cases; high, 50 cases; and not determined, 4 cases), and calcification (100% consensus: yes, 110 cases and no, 80 cases) were recorded. Statistical analysis demonstrated that the Shimada classification system (90% consensus; 3-year event free survival: 85% for the group with favorable histology and 41% for the group with unfavorable histology; P = 0.31 x 10(-9)) had a significantly stronger prognostic effect than individual features and other combinations. CONCLUSIONS: The International Neuroblastoma Pathology Classification, a system based on a framework of the Shimada classification with minor modifications, is proposed for international use in assessing NTs.
Brain Neoplasms↗
Somatization, anxiety and depression as measures of health-related quality of life of children/adolescents with cancer.
This descriptive study of health-related quality of life of children with cancer compared children/adolescents', parents' and teachers' ratings for somatization, depression and anxiety to determine if there were significant correlations among respondent scores. In addition, the percentage of agreement among respondents and significant differences based on age, gender, use of cranial radiation and treatment status were measured. Forty-three children/adolescents with cancer, currently receiving therapy for at least 1 year or who had completed therapy for no more than 3 years (excluding children who had received bone marrow transplants or who had brain tumors), were recruited, with a parent and teacher, from 3 university medical centers. The Behavioral Assessment System for Children questionnaires for children/adolescents, parents and teachers were used. Parents reported a higher level of depression for the children/adolescents with cancer than did the teachers or the children/adolescents themselves. Parents reported a higher level of anxiety for the children/adolescents than did the teachers. High positive correlations were found among scores from parents and teachers and among scores from parents and children/adolescents for the anxiety and depression but not somatization subscales. Children/adolescents and teachers had high, positively correlated scores only for the depression subscale. High, positive correlations were found between somatization, anxiety and depression within each group of respondents. A significant percentage of agreement between all respondents on ratings for at-risk status was obtained only for the depression subscale. Age was the only variable found to have an influence on scores and only for the anxiety subscale.
Adolescent↗
Intensification of therapy using hematopoietic stem-cell support for high-risk neuroblastoma.
The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group and the Pediatric Oncology Group have agreed upon common prognostic criteria for treatment stratification. We summarize below the prognostic classification and treatment approaches that have improved the overall outcome for children with advanced neuroblastoma. Intensive induction therapy, myeloablative therapy, hematopoietic stem cell purging, and post-transplant therapy for minimal residual disease all have an important role in the treatment. Possible future improvements may incorporate more tumor-specific therapy with targeted radiotherapy, monoclonal antibodies, tumor vaccines, and differentiating agents.
Antineoplastic Combined Chemotherapy Protocols↗