Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study.

PURPOSE: The objectives of this study were to evaluate the feasibility of reducing therapy, while maintaining treatment efficacy, in the context of a cooperative group clinical trial that allowed for clinical staging in early stage Hodgkin disease (HD). PATIENTS AND METHODS: Between August 1992 and December 1993, 51 eligible children < or =21 years of age, 31 male and 20 female, were enrolled in this study which was designed for low stage (IA, IIA, IIIA1) HD. Laparotomy and surgical staging was optional. Five postpubertal patients with Stage IA and IIA disease received only involved-field radiation therapy. The other 46 patients, who form the basis of this report, received combined modality therapy consisting of four courses of doxorubicin, bleomycin, vincristine, and etoposide (DBVE) followed by 2,550 cGy involved-field irradiation. RESULTS: With a median follow-up of 8.4 years, the 6-year overall and event-free survival rates for the 46 patients treated with combination therapy were 98 +/- 2% and 91 +/- 5%, respectively. All patients achieved remission after completion of therapy. There have been four recurrences and a remission death due to gunshot wound. Combined modality therapy was well tolerated. Predominant side effects were gastrointestinal and hemopoietic. There have been no clinically significant cardio-pulmonary side effects so far. CONCLUSION: In clinically staged children with early-stage HD, DBVE and low-dose involved-field irradiation was effective therapy with tolerable side effects and reduced potential for long-term adverse events.

Lymphocyte predominant Hodgkin disease: clinico-pathologic features and results of treatment--the Pediatric Oncology Group experience.

PURPOSE: In this report, the Pediatric Oncology Group (POG) experience with lymphocyte predominant Hodgkin Disease (LPHD) in children is reviewed. MATERIALS AND METHODS: From 1984-1993, the POG conducted 3 clinical trials for advanced stage HD and 2 for early stage HD. There were 26 cases of LPHD in 613 patients in these trials. Patients' ages ranged from 3.1-17.8 years (mean of 12.9 years). There was a marked male predominance. RESULTS: Histologic subtypes were 17 nodular, 8 diffuse pattern; 1 was indeterminant. The sites involved at diagnosis were primarily the peripheral lymph nodes. Fourteen patients had stage (S) I disease; 9 had SII; 3 had SIII; there was no SIV disease. Only 4 of 26 patients had B symptoms. All 26 patients achieved complete remission, 10 with radiotherapy, 6 with chemotherapy and 10 with combined modality therapy. Treatment was not uniform since patients were registered on different protocols. Event-free survival after 5 years was 86.5 percent. Two patients developed and succumbed to large cell, T-cell type, non-Hodgkin lymphoma (NHL). CONCLUSIONS: Optimal treatment for LPHD should focus on efforts to limit the risk of second malignancy.

Treatment compliance in childhood and adolescence.

Experience reveals that there is significant noncompliance with self-administered medication, especially in chronic conditions such as cancer. Noncompliance transcends the boundary of disease categories and age group. However, this is most prevalent during the adolescent years when the process of transition from parental dependency to autonomy produces confusion as to who is responsible for administration of medication. Noncompliance can result in the misjudgment of efficacy of a drug or regimen that may necessitate additional tests, alteration of dose, treatment course, and hospitalization. Currently in the United States, a large percentage of pediatric cancer patients are treated according to research protocols. In a research setting, noncompliance can result in erroneous or inconsistent findings, potentially affecting investigational results. With the availability of venous access ports and sophisticated, yet easy-to-operate pumps, increasingly, it is possible to administer parenteral medications at home. This adds a new dimension to the self-administration of medication that previously concerned mainly oral therapy. Various factors concerning the patient, disease, health providers, and treatment characteristics determine how well a given regimen is adhered to. Because a significant number of determinants are involved, it is often not possible, with any degree of certainty, to identify noncompliers or to predict the level of patient adherence to the treatment. Major factors in any successful therapy include the availability of effective medications and compliance with therapy regimen. With the advent of more successful treatments for childhood and adolescent cancer, the compliance factor is gaining greater importance because therapy currently is given with curative, rather than palliative intent. The availability of questionnaires, tests, and devices can help, to some extent, examine the degree of patient compliance. Family and social support, individualized programs, reminders to reduce forgetfulness, personalized needs assessment, and education can reduce noncompliance. Compliance is a complex and multifaceted issue that is still poorly understood and requires further investigation.

Reversal of C1300 murine neuroblastoma multidrug resistance by cremophorEL, a solvent for cyclosporin A.

We previously developed a homoharringtonine resistant C-1300 neuroblastoma cell line with cross-resistance to adriamycin and increased levels of p-glycoprotein, and showed that drug resistance could be reversed in this cell line by cyclosporin A. The present study shows that cremophor EL, a parenteral vehicle for cyclosporin A, can also completely reverse this multidrug resistance in a clonogenic assay system. Cremophor EL incubated with resistant cells for up to six days did not reduce levels of p-glycoprotein. Intracellular homoharringtonine analysis using HPLC revealed increased drug accumulation in resistant cells treated with cremophor EL. The increased drug level was not due to blocking of drug efflux commonly seen in other multidrug resistant models. The data suggest that resistance modulation with cyclosporin A should be interpreted with caution when cremophor EL is a solvent. Our work suggests cremophor EL, a relatively nontoxic lipophylic solvent, may have a direct effect on membrane permeability, although other mechanisms cannot be ruled out.

1-beta-D-arabinofuranosylcytosine conjugates of ether and thioether phospholipids. A new class of ara-C prodrug with improved antitumor activity.

The 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemia in vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octa-decyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01-0.04 microns). Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.

Modulation of drug resistance in homoharringtonine-resistant C-1300 neuroblastoma cells with cyclosporine A and dipyridamole.

The development of resistance accounts for therapy failure in the majority of advanced cases of neuroblastoma in children. A new transplantable murine C-1300 neuroblastoma cell line was developed in vitro, by repeated exposure of a sensitive cell line to increasing, but sublethal, doses of Homoharringtonine (HHT). The ED50 of the highly resistant cells for HHT, using a standard agar colony assay, is 480 ng/ml, compared with 13 ng/ml for the sensitive parental line. The resistant cells have cross-resistance to a number of other agents, including adriamycin, vinca alkaloids, melphalan, and CCNU. Western blot analysis revealed progressive increases in P-glycoprotein, parallel to the graded development of resistance with a 29-fold elevation in the highest resistant cells. High-performance liquid chromatography (HPLC) indicated that resistant cells have a significantly lower uptake of HHT than parental sensitive cells. cyclosporine A (CsA) and dipyridamole (DPM) could modulate the acquired resistance and completely restore the cytotoxic effects of HHT and adriamycin as determined by the clonogenic assay. The reversal of resistance by CsA and DPM was dose dependent. With the relative low toxicity of dipyridamole and CsA in doses required for modulation of resistance, these agents may be candidates for clinical utilization in chemotherapy of resistant neuroblastoma.

Toxicity of high-dose cytosine arabinoside in the treatment of advanced childhood tumors resistant to conventional therapy. A Pediatric Oncology Group study.

Experience with high-dose cytosine arabinoside (HDAC) in pediatric solid tumors is limited. Sixteen children with solid tumors resistant to conventional therapies were registered in a pilot Pediatric Oncology Group (POG) study that required the administration of HDAC at 3 g/m2 every 12 hours for four doses. There were four cases of rhabdomyosarcoma, two cases of fibrosarcoma, four cases of neuroblastoma, and one case each of germ cell tumor, Wilm's tumor, retinoblastoma, hepatocellular carcinoma, Ewing's sarcoma, and Burkitt's lymphoma. All eligible patients had advanced diseases and had previously received extensive chemotherapy. Thirteen patients received one course of HDAC and three patients received two courses of HDAC. Due to prior treatments, patients had less than normal marrow reserves. Short-term toxicity included nausea, vomiting, suppression of hemopoiesis, drug fever, and increased blood urea nitrogen (BUN), creatinine, and liver enzymes. All evaluable patients recovered from their toxicities. There were no drug-related deaths. None of the patients had neurologic problems, including the only patient with prior irradiation to the skull. With the above schedule, HDAC appears to have manageable toxicity.

Vocational adjustment and general well-being of young adults with IDDM.

The vocational experiences and general well-being of 58 young adult subjects (mean age 24.3 yr) with insulin-dependent diabetes mellitus (IDDM) diagnosed during their adolescence were compared with that of 55 healthy matched control subjects with linear logistic discriminant function analyses. Assessment measures included the Rand General Well-Being Scale and the Rand Functional Limitations and Physical Abilities Batteries. Diabetic subjects, on average, reported significantly lower general well-being than control subjects, particularly in terms of health-related fears and feelings of depression. However, diabetic subjects did not report a pervasive functional deficit relative to control subjects and experienced similar employment rates and problems in the workplace. These results suggest that this group of young adult diabetic subjects has adjusted well to the demands of the workplace despite lower reports of general well-being. The results are discussed in light of relevant sampling issues.

Central Nervous System (CNS) Involvement in Acute Nonlymphocytic Leukemia (ANLL).

The incidence of central nervous system (CNS) involvement and effects of therapy were reviewed in 42 consecutive pediatric patients with acute nonlymphocytic leukemia (ANLL). The morphology of ileukemic cells was considered M1 in 13, M2 in 7, M3 in 5, M4 in 8, and M5 in 9. Two patients with M5 morphology presented with CNS disease at diagnosis. Systemic Ara-C treatment was included as a mainstay of remission induction and maintenance program for all patients. With the exception of the M5 group, none of the patients received direct CNS prophylactic therapy. There was a 0% incidence of CNS relapse: in this group of patients. Median duration of remission for all patients (excluding the M5 group) was 33 months. This experience may indicate that systemic treatment with Ara-C may provide some degree of CNS prophylaxis in ANLIL.

Attributions of responsibility in adolescent cancer patients and their parents.

Attributions of responsibility have been shown to be important determinants of illness behavior in adults. This study examines the salience of attributional judgements among adolescents with cancer. Patients and their parents were categorized according to their attributions of responsibility for the cause of and solution to the adolescent's health problems into one of four attributional models. Of the four possible models, only two were represented: the medical and compensatory. Only 37.5% of parent/child pairs were concordant for model choice. Patients whose attributions conformed to those of the compensatory model sought more information (F = 5.1, (P = .03), were satisfied with the information supplied (F = 3.5, P = .07), and expressed the belief that a greater percentage of prescribed medications needed to be taken if a cure was to result (F = 4.1, P = .05). Side effects were more often experienced by patients whose responsibility attributions exemplified the medical model (F = 5.09, P = .03). Model concordance did not relate to parent/child agreement on health-related beliefs, patient age, sex, or compliance measures (P greater than .05). No relationship was found between parent-child model concordance and patient's self-reported medication compliance. The present data do not support the notion that attributions of responsibility for cause and solution of cancer should be important targets of interventions designed to increase medication compliance among cancer patients.

Long-term vocational adjustment of cancer patients diagnosed during adolescence.

Long-term vocational achievements of 40 survivors of cancer diagnosed during adolescence were examined and compared with 40 healthy sex-matched and age-matched controls. Patients' ages at diagnosis ranged from 13 to 19 years (mean, 16.15). Study subjects had survived cancer for over 5 years and were on no cancer therapy. Assessment measures included the Rand General Well-Being Scale, the Rand Functional Limitations and Physical Abilities Batteries, and a semistructured interview. The relation of physical disability and limitations caused by cancer to patients' achievements also was evaluated. Although cancer patients, on the average, were more concerned about their health and reported lower general spirits than controls, no differences were found between control and study groups with regard to overall general well-being. More cancer patients than controls reported that their health limited their ability to engage in vigorous activities. A greater functional deficit was found among unemployed than employed cancer patients. Employers and co-workers often were aware of the patient's diagnosis (85% and 67%, respectively). Cancer patients reported disease-related discrimination in hiring (7.4%), induction into the military (66.7%), and obtaining health, life, and disability insurance (31.5%). There was no significant relationship between health status and employment. Nevertheless, cancer patients had a higher average income than controls. Sixty-four percent of patients believed that changes in certain physical features of the workplace were necessary to facilitate readjustment to the job. Despite the disabilities experienced by cancer patients and generally negative public attitudes, long-term survivors have a good outlook on life and are competitive members of the workplace and society.

The significance of the ratio of blood to marrow hematopoietic progenitors (CFU-GM and CFU-GEMM) in relation to disease state of patients with acute lymphoblastic leukemia.

We studied a total of 143 patients with 231 assays of CFU-GM, of these, 45 patients were studied with 58 simultaneous assays of CFU-GEMM in an attempt to correlate progenitor colony growth with disease state. Blood and marrow leukocytes were cultured in a standard methylcellulose culture system using normal human leukocyte colony stimulating activity. Results are expressed as natural logarithm of the ratio of blood colonies to marrow colonies. A high ratio of blood to marrow (greater than 1) was seen in active disease while a low ratio occurred during remission. Eighty-seven per cent of CFU-GM matched pair samples with active disease had high ratios while less than 1% of remission samples were high. In addition, patients with suspected relapse or relapse up to 14 months after this test often had high ratios indicating this test could be of prognostic value. It is not known if this effect of ALL is unique to ALL or if it occurs as a reaction to any hematopoietic stress.

Adjustment to amputation among adolescent oncology patients.

With increased patient survival, the psychosocial consequences of amputation in cancer patients has become increasingly important. The following study examined the psychosocial correlates of amputation in 16 male and 17 female Brazilian adolescent patients aged 10-20 years who had lost a limb to cancer. Interviews were conducted within 12 months of amputation. Eighty-two percent indicated that they were involved in preoperative decision making, but only 58% understood the limitations in functioning after undergoing an amputation. Before surgery, the most frequently chosen confidante was the mother, followed by a sibling, staff member, and a friend. The major postoperative problems in these patients were walking, pain, and social issues. Overall, 75% of the amputees felt they were independent in and out of the home. Most individuals (66.6%) had, but fewer (58%) wore, their prosthesis. Prior to amputation, 30 patients were enrolled in school and 13 had a job. Of 15 who returned to school, 67% could not keep up with the school work and 93% had problems getting along with their classmates. Of five patients who returned to their jobs, no one reported discrimination in hiring or promotion; however, four workers felt they had lost a job because of their amputation, and two reproted having to change jobs. Many had altered their lifestyles to suit their disability, but the social and educational adjustment of these patients appears promising. Proper education of school faculty, classmates, and medical staff may enhance the adjustment of adolescent cancer amputees.

Osteosarcoma.

Osteosarcoma is the most common bone tumor of children and adolescents. The peak incidence of the disease is in the 15 to 19 year age group. The disease is more commonly seen in males than females. While several factors, including exposure to radiation, genetic disorders such as retinoblastoma, and high rate of bone growth, have been associated with osteosarcoma, in most cases no definite etiology can be established. Osteosarcoma usually originates in the metaphyseal region of long bones and extends through the cortex, causing varying degrees of bone destruction and expansion of periosteum. The radiographic appearance caused by this process is often referred to as "sun burst" sign. Positive diagnosis of osteosarcoma is made by histopathology. The histopathological classification of osteosarcoma can also predict the degree of aggressive behavior of this tumor and thus has prognostic significance. Surgery, including amputation or limb-salvage procedure, is the mainstay of treatment of osteosarcoma. It is now unequivocally established that adjuvant chemotherapy will prolong the survival of patients with this disease. Chemotherapy agents often used include platinum derivates, methotrexate, vincristine, cyclophosphamide, adriamycin, actinomycin D, bleomycin and DTIC. Depending on surgical decision, these agents can be used prior to or after the operation. Immediate fitting with prosthesis and provision of appropriate medical and psychological support in the care of these patients is essential.

Self-reported depression in adolescent cancer patients.

The prevalence of depression was studied, using the Beck Depression Inventory (BDI) and Schedule for Affective Disorders and Schizophrenia (SADS), in a sample of 30 adolescent cancer patients. BDI scores revealed that 26 patients (87%) were not depressed, 4 (13%) were moderately depressed and no one had severe depression. Similarly, SADS data indicated no history of depression in 75% of the sample, and histories of minor and major depression in 14 and 10% of the sample, respectively. Females scored significantly higher (p less than .05) than males on BDI physical, but not psychological, items. The average response to BDI physical items was significantly greater (p less than .05) than to psychological items, suggesting that somatic symptoms are more salient than psychological symptoms of depression among adolescent cancer patients. Overall, however, as compared with norms, the rate of major depression among adolescent cancer patients is not greater than that for the population at large. These data do not exclude the possibility of masked symptoms, which only under stringent conditions will become obvious.